★★★★★
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. '
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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 of melatonin in humans.
Art
Melatonin
★★★★★
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
