Parkinson's Disease - Editor's Choice

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. It is also suggested that earlier application of melatonin in the disease may be even more beneficial than application in advanced disease states.

https://www.frontiersin.org/articles/10.3389/fneur.2023.1265789/full

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. '

::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::

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 of melatonin in humans.

Art

Now I would like to talk about one of my favorite supplements, melatonin, that a recent randomized, double-blind, placebo-controlled study showed was beneficial for PD patients after just 12 weeks of supplementing only 10 milligrams per night! Yes, finally, a quality human study confirming that melatonin is beneficial for people with PD.

This study showed multiple benefits in patients that include the following. Using standard testing, melatonin showed improvement in anxiety, depression, total antioxidant capacity, increased glutathione, and improved UPDRS Part 1 test results! Melatonin also significantly lowered the inflammatory marker, hs-CRP, or high sensitivity C-Reactive Protein and inflammatory TNF-a while lowering LDL cholesterol and improving insulin resistance! Some of these improvements are suggestive of the idea that a more extensive study and or higher dosing may produce even better results because many of these improvements imply a reduction in total oxidative stress and oxidative stress is one of the most damaging factors in PD that destroys dopaminergic neurons and other cells in the substantia nigra of the brain.

To say I am excited that this study would be an understatement! Studies showing benefits like these in humans with PD from a single supplement are almost non-existent. Hopefully, they will follow through on this study with similar studies using pharmacological dosing of melatonin and more extended length studies.

While this study is very good and confirmed that melatonin can be beneficial in people with PD, it leaves many unanswered questions such as what would have happened if the study had been 24 weeks long instead of 12 as 12 weeks is very short for a study like this? Would the benefits range increase, would the benefits stay the same or increase the level of improvement seen? What would have happened at higher dosing?

Remember that Dr. Shallenberger is using dosing that is as much as 36 times higher than what was used in this study in some of his patients, and he gives all of his patients 180 mg of melatonin per night in the form of three 60 mg capsules in the evening. He considers this a preventative dose.

Overall, I feel this study has opened a door that has been closed for too long, and hopefully, there will be follow up studies to answer these questions! Here is a link to that very recent study abstract :

https://pubmed.ncbi.nlm.nih.gov/32417629/

Art

I feel like a different person now. Still far from who I was before PD but now I can do my daily activities slowly and no longer suffer anxiety, off the Xanax I took for 3 1/2 years, and minimal depression. I get the blues on occasion. I only take Selegiline 5mg twice a day as a prescribed medication. I was prescribed 7 medications previously.

I started high dose B1, Thiamine, June 2018, taking 1/4 teaspoon in water, twice a day. I did not notice any change in my symptoms. I increased it to 1/2 teaspoon in water, twice a day, still no change. I continued taking it anyway. I then purchased capsules, 500mg. I take two, twice a day. I started noticing that I was using my right hand for things I could not do before. The changes have been subtle but to me significant, giving me hope. I have more energy and feel more alive. My movements are more fluid.

I must add that I also changed my diet. I have been vegetarian since I was 16 but now I am, or try to be, gluten free, dairy free, plant based diet. I suffer chronic pain and wanting to decrease inflammation. I also added the use of low level red light therapy. Not sure what is working but I feel I have turned a corner and instead of declining I feel I'm improving, very slowly.

Thank you.

Hi Mary,

I see you are writing about your brother again. It is good that he has an advocate looking out for his better interest. I have several friends with PD and I have done a lot of reading on their behalf looking for alternatives, since the standard treatment by our medical community does absolutely zero to halt or even slow disease progression. The currently available PD prescriptions only treat symptoms and can not alter disease progression, but some of those prescriptions can actually add to PD symptoms.

In researching for my friends with PD, I generated a list of over 75 supplements that have potential to be helpful for people with PD. Two of the main points that many studies high light is that excess inflammation and excess radicals, damage the human body and seem to feed the progression of PD so consequently many protocols for PD are aimed at reducing radicals of many types by taking some of the more potent free radical fighters such as alpha lipoic acid, n acetyl cysteine, melatonin, selenium and the like. For inflammation, the ability of these potent antioxidants to neutralize different types of radicals can lessen inflammation and then there are many antinflammatory herbs and supplements that can help to lower the overall inflammatory state associated with PD. Some of the better known ones are curcumin/meriva, boswellia serrata extract/5 Loxin/Akba/Apres Flex, pine bark extract, egcg/green tea, mangosteen, high grade fish oils, magnesium in many forms that are more bioavailable than magnesium oxide. Topically applied mag oil/ magnesium chloride is one good one because for some people when applied to the skin it is calming and tends to relax stressed muscles. Another form called magnesium l threonate is purported to effectively cross the blood brain barrier and is thought to be about the best for targeting the brain, which should be a good thing for PD patients. Many of these supplements may have synergy with one another and could potentially slow the disease progression which is good since the prescription meds can't. I think in a previous reply to you, I mentioned one study that suggested that vitamin D may have slowed or even halted disease progress for one year. That alone is worth making sure that your brothers vitamin d level is replete and closer to the top of the reference range than to the bottom. Reference range for 25 OH d level is 30 to 100 ng/ml. Most people are insufficient (blow 30 ng/ml) or deficient (below 20 ng/ml).

On a more important note, in all of the reading I have done regarding PD, I came across a few small studies by two different medical groups that utilized a common vitamin at very high dose that was administered by intramuscular injection. These two groups were in very different areas of the planet and were not associated in any way, but their clinical findings were very similar. One group was in California and the other was in Italy. Both groups came to the conclusion that their specific treatment, not only halted disease progression in PD patients, but actually reversed motor and non-motor symptoms! I know that is a heck of a claim for PD and so it made me want to contact either of these two groups to find out if they were accepting patients.

I tried to contact the California group first since that seemed to be a simple thing to do, but I was told that the neurologist who was the lead researcher for his group, had passed away and none of the other researchers from his group were continuing the research so it essentially died with him.

Failing that I decided I would try and contact the research group in Italy by email. To my surprise, the lead research neurologist contacted me and sent me three clinical research studies that he had done over the past 5 or 6 years. I told him about my friends with PD and he told me it would be ideal if they could come to Italy to his clinic, but he said that even if they couldn't come to his clinic, he could still try to treat them via email. He said he needed a copy of their medical records and a short video of them talking and a short video of them walking. He said the videos were not for him, but rather for the patient to watch every now and again so they could have a basis for comparison as time passed.

Only one of my friends decided to try this doctor's protocol, but the first problem he ran into was that none of his doctors were willing to give the twice weekly injections and he even checked in Mexico to see if he could get them done there, but he didn't have any luck there either. At that point, I wrote the doctor again and asked him if it would be possible to take the supplement by topically applying it to the skin with DMSO? He wrote back and said there was no need to go through the inconvenience of having to apply the supplement with DMSO, as my friend could just take a very high dose of the vitamin supplement on a daily basis and while he said it might not work as well as the injections, it would probably halt the disease progression and likely reverse some of the symptoms. He told me he had treated several of his PD patients who were opposed to twice weekly injections with this oral method and he said it worked very well for them.

Armed with all of this information, one of my friends decided he wanted to give it a try and so he first ordered the supplement in a pure bulk powder form with no additives. He started on the protocol that the doctor set out for him. He was a bit hit and miss at first, because he started to feel improvement in the first week and he started slacking off on his dosing which soon had him feeling bad again. I should mention here that the first symptom that improved for him was anxiety. He said this anxiety made him feel bad everday of his life and within two weeks of taking his supplement mixed in Gatorade, his anxiety level dropped way down to where he felt pretty comfortable again.

In any case, my friend started on this supplement last November and is still taking it because he simply says he feels better with it and without it he could tell that his PD was definitely progressing at a fairly quick pace whereas now he does not feel that his PD is progressing and some of his symptoms are better.......including the anxiety.

One of the reasons that I felt my friend would slack off on taking his supplement was because he has to mix the bulk powder in Gatorade and this is not always convenient, so I found some high dose capsules of this vitamin and he started taking those on a more regular basis than the powder, but recently he told me that he wasn't positive, but he feels like the bulk powder is more effective than the capsules and even though it is a little more trouble to take the bulk powder, he is going to go back to it when he runs out of the capsules. One possible reason that the powder may be working better for him is because it has no fillers of any type while the capsules are gelatin and then there are additives in the capsules for various reasons which may work against the active compound.

Mary, if you want to know more about this, I can find the links for the studies I have seen as well as a couple of YouTube videos that show some of this neurologist's patients before treatment and awhile after treatment. In corresponding with this doctor he told me he has treated over 100 PD cases with this protocol and only had one patient who could not tolerate it as she would throw up right after she got an injection.

Lastly and also of importance, this is not a cure and the patient still needs to take their regular meds. If you stop taking the vitamin, all symptoms return and the disease continues to progress again. Based on what my other friends with PD have told me, their doctors are not open to this whole idea and will definitely "not" do the injections for them. One of my friends took all of the studies I gave him so he could show them to his doctors to see if they would monitor him if he started taking the supplement and they flat out told him no and not only that, they wouldn't even look at the studies........they said they had no time to be reading worthless studies, but they are quite fine with prescribing drugs for him in which they know he will end up a drooling, shaking and demented mess!

Art

The vitamin is vitamin B-1 or thiamine and he uses it at high dose as intramuscular injections in his office in Italy. Unfortunately, these I.M. injections are somewhat difficult to get here in the states and even harder to get your doctor to prescribe them and monitor you. The medical community here in the states is resistant to the whole idea.

The neurologist in Italy is Dr. Costantini and he has been using this protocol on his patients for 5 years+ and the results are fairly remarkable. In patients who have been on the protocol for 5 years, in addition to the symptom improvements, he has seen no progression of the disease during these past 5 years and one of his patients who had a datscan done showed no apparent progression on a recent datscan!

You are probably thinking, well, he's probably only treated a few patients with this protocol, but he has actually treated over 2,500 patients with thiamine im injections and the results have been very good as well as quite durable over time! He also has another group of over 200 patients from around the world that he treats remotely via email. I've been in contact with Dr. Costantini for about three years now after reading some of his studies on PubMed while researching for three of my friends who have PD as well as two acquaintances with PD.

I've read quite a bit on the subject and Dr. Costantini has been very helpful in keeping me up to date on how his research is going and he found that oral thiamine can be used effectively also! This makes his protocol very useful to many more PWPs around the world because of its easy availability at relatively low cost. Thiamine has many health benefits that are rarely mentioned and is also effective for a few other neurolgical conditions as well as MS! It does require a very high oral dose each day and is compatible with most PD meds adding to its versatility for PWPs!

What I have found from approximately 45 people who are taking his protocol that I am following is that one of the hardest parts to this protocol is finding the correct dose for each individual patient which has taken up to 6 months and varies significantly from patient to patient. In these 45 patients, the ones who have gotten the best results are those who have worked with Dr. Costantini continuously through this initial period while trying to find the correct dose. Once the correct dose is found, then it is just a matter of taking it everyday along side your regular PD meds. The results that these 45 people have gotten are impressive! Everyone is different so results can vary from patient to patient. Out of these 45 patients all say they will continue to take the vitamin for the rest of their life!

PD is simply a horrible disease and the current meds only address symptoms while doing nothing to slow disease progression, while thiamine in Dr. Costantini experience with over 2,700 patients shows the potential to affect disease progression positively as patients who have been on it for over five years and then stop taking it only show symptoms similar to or better than when they started!

If anyone is interested in this protocol or has questions, I will post more about it as well as how to Contact the doctor.

Art

I wrote the following on another health forum and it was specifically with Parkinson's Disease in mind but the information applies to many health issues and may be useful for general health improvement!

::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::

There are many potential reasons why probiotics, prebiotics and synbiotics may be useful for PWPs. Although the great majority of PD / probiotic studies involve animals, there are many human studies that show benefits that would definitely be useful for PWPs!

This video brilliantly explains why glutathione is important for PWPs:

https://www.youtube.com/watch?v=KWuOezgVHdI

In this first study, it is shown that probiotics increase glutathione production.......something that every PWP can definitely use because glutathione is a highly potent antioxidant and radical scavenger which is often at suboptimal levels in PWPs! In studies, glutathione has shown great benefit for PWPs and one doctor has used glutathione to very good effect in some of his PD patients as has already been shown in other posts here on this forum. The problem with glutathione is that you can not just take a supplement of it because it will not do well as it passes through the gut. There are even lypospheric glutathione products out there to try and overcome the gut issue. There are also injections and infusions, but these are not very practical for long term use, but probiotics are doable for this purpose.

https://www.ncbi.nlm.nih.gov/pubmed/21058502

In these next studies, it is shown that probiotics reduce high sensitivity C reactive protein or hsCRP, which is a common marker used to determine inflammation levels. PWPs can definitely have a use for reduced inflammatory levels which are elevated and neuro damaging in PWPs.There are B-vitamins that can help reduce hsCRP, but one or two are sometimes contraindicated with certain PD meds.

https://www.ncbi.nlm.nih.gov/pubmed/25453395

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4573418/

https://www.ncbi.nlm.nih.gov/pubmed/23899653

Two very common symptoms of PD is depression and anxiety and these two do not get discussed enough considering how prevalent they are in PWPs. The next study shows how probiotics can reduce both!

https://www.ncbi.nlm.nih.gov/pubmed/25470391

Inflammation is a major player in PWPs who generally have elevated levels of inflammation, but other things can add to the total inflammatory load in the body, such as arthritis. In PD, it is well established that exercise is highly beneficial, but arthritis makes exercising difficult if not impossible for PWPs. On that note, the following study suggests that probiotics can lower the inflammatory load and symptoms related to arthritis!

https://www.ncbi.nlm.nih.gov/pubmed/24355439

Along those same lines, any disease that raises inflammation and oxidatative stress levels is going to be counter productive or disease worsening for PWPs and diabetes would be one such common disease. The following study suggests that probiotics can ameliorate many symptoms associated with diabetes including inflammation, insulin resistance, oxidative stress and reduce intestinal permeability, a very common problem in PWPs, as many of you already know! These activities of probiotics also improve insulin sensitivity, which anyone with diabetes can truly appreciate the value of. Improved insulin sensitivity can help to lower the total inflammatory burden of the body!

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4078018/

Since it is already established that moderate to heavy aerobic exercise can be quite beneficial for PWPs, something that will help reduce the muscle damage associated with this type of exercise would be very useful for PWPs in order to get the most out of the exercise you do, and probiotics may be just the thing according to this next study.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4963221/

Neurodegeneration is a hallmark aspect of PD and probiotics have a broad spectrum of health benefits of which neuroprotection is one along with antioxidant improving, oxidative stress lowering, GABA increasing and increased dopamine levels as outlined in the following abstract!

https://www.ncbi.nlm.nih.gov/pubmed/26450608

The following two studies add to that line of thinking.

https://www.ncbi.nlm.nih.gov/pubmed/29492848

https://www.ncbi.nlm.nih.gov/pubmed/29154736

It is well known that many PWPs have a disturbed gut microbiome and constipation and other gut disturbances are common symptoms of this disease. Probiotics have the ability to help in this area also according to the following.

https://www.ncbi.nlm.nih.gov/pubmed/21587143

https://www.ncbi.nlm.nih.gov/pubmed/19083380

Psychological stress can worsen symptoms of PD and probiotics can help to ameliorate psychological stress according to the following abstract.

https://www.ncbi.nlm.nih.gov/pubmed/25224893

Given the typical age range of PWPs, it can be considered that this group may also have elevated LDL cholesterol, VLDL, and tryglycerides while having reduced HDL cholesterol (the good one). Doctors typically prescribe statin drugs to try and normalize cholesterol levels, but statins are well known for their bad effects on muscle tissue and muscle pain in some people which can be a major setback for PWPs. Probiotics are quite effective at not only lowering LDL, VLDL and tryglycerides, but also elevating HDL cholesterol according to the following study!

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3984795/

PWPs in general have a disturbed microbiome that can create other health issues which I discussed previously in an earlier post about mannitol at this link:

That post discussed the fact that prebiotics like mannitol can increase the production of thiamine, hydrogen sulfide (H2S) and butyrate of which all three are important in terms of symptom relief in PWPs........hugely important!

There is much more I can say about probiotics, prebiotics, synbiotics, fermented foods and the like in terms of overall health benefits, but I think the above is more than enough to highlight the potential of these health supplements as it applies to PWPs and other disease states!

If your neurologist told you he/she could prescribe one drug that has the potential to lower hsCRP, raise glutathione, lower inflammatory markers, increase insulin sensitivity, reduce or eliminate constipation, restore the gut microbiome to a healthier state, increase dopamine levels, reduce stress, reduce anxiety, reduce depression, reduce tryglycerides, increase HDL cholesterol, act as a neuroprotectant and help with arthritis symptoms and diabetes, would you tell your neurologist that you are not interested?

Something that PWPs have to deal with is the amount of pills they have to take everyday, so finding pills that have multiple benefits in one pill is useful and can potentially make it easier to stick to your regimen while reducing symptoms with minimal side effects, if any!

Art

https://www.earthclinic.com/cures/vitamin-d-for-parkinsons.html