In this new review abstract (August 23, 2024), it is shown that people with PD have blunted melatonin levels resulting in reduced neural protection and increased daytime sleepiness among other problems as discussed here :
Here is a relevant quote from the review article :
' MTN is neuroprotective in various neurodegenerative diseases, including Parkinson's disease (PD). MTN circulating level is highly blunted in PD. However, the underlying causes were not fully clarified. Thus, the present review aims to discuss the potential causes of blunted MTN levels in PD. Distortion of MTN circadian rhythmicity in PD patients causies extreme daytime sleepiness. The underlying mechanism for blunted MTN response may be due to reduction for light exposure, impairment of retinal light transmission, degeneration of circadian pacemaker and dysautonomia. In conclusion, degeneration of SCN and associated neurodegeneration together with neuroinflammation and activation of NF-κB and NLRP3 inflammasome, induce dysregulation of MTN secretion. Therefore, low serum MTN level reflects PD severity and could be potential biomarkers. Preclinical and clinical studies are suggested to clarify the underlying causes of low MTN in PD. '
One potential cause of reduced melatonin secretion maybe the fact that people with PD are thought to have lower levels of serotonin, a precursor of melatonin. The following link to a human study discusses how PwP have lower serotonin marker levels :
' Lately, increasing attention has been given to neuronal degeneration outside the nigrostriatal pathways and to other neurotransmitter systems involved in PD. As reviewed by Huot et al.,10 a growing amount of research supports the presence of serotonergic deficits in PD. Post-mortem, biochemical and neuroimaging studies point to a reduction in various serotonin associated markers, with a regional distribution distinct from that of dopamine. Such deficits in the serotonin system are speculated to account for some of the non-motor symptoms commonly found in PD. '
I bring these studies up to highlight the potential of melatonin lotion (ML) to offer a very significantly greater duration of release time in the range of 24 hours compared to the typical 5 hours and done for oral melatonin as I discussed in the following link as well as an explanation of how I easily make melatonin lotion :
Please consult your doctor or other healthcare professional to make sure ML will be safe for you as well as compatible with all of your other prescription medications as ML does go systemic.
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Thank you. I wonder if this type of melatonin lotion would aggravate my husband's restless legs? I guess I could make a weak version and see if it bothers him.
Unfortunately I have not had any experience with anyone testing ML with restless leg syndrome (RLS) so I don't know the answer to your question.
If your husband decides to test ML, I would really appreciate knowing how it affects him and the RLS!
One other thought, since RLS is mainly a problem between 10:00 pm and 4:00 am, even if it bothers his RLS, he may be able to use it during the day if it helps his pains.
It has been three weeks and I was wondering if you ever tried the melatonin lotion to see if it had a negative or positive impact on your husband's RLS.
Very interesting, this would explain a lot... Such as how what seems to me reasonable doses are ineffective and my worry about becoming overdosed by using some of the higher doses discussed by some folks here.
One thing that I have not discussed extensively about melatonin on this forum is its role in the human gut, which is especially important for people with PD because gut microbiome dysbiosis is a hallmark of PD as discussed here :
' Parkinson’s disease (PD) is the second most common neurodegenerative disease characterized by motor dysfunction. Growing evidence has demonstrated that gut dysbiosis is involved in the occurrence, development and progression of PD. Numerous clinical trials have identified the characteristics of the changed gut microbiota profiles, and preclinical studies in PD animal models have indicated that gut dysbiosis can influence the progression and onset of PD via increasing intestinal permeability, aggravating neuroinflammation, aggregating abnormal levels of α-synuclein fibrils, increasing oxidative stress, and decreasing neurotransmitter production. The gut microbiota can be considered promising diagnostic and therapeutic targets for PD, which can be regulated by probiotics, psychobiotics, prebiotics, synbiotics, postbiotics, fecal microbiota transplantation, diet modifications, and Chinese medicine. '
Further, melatonin works to ameliorate many of these negative gut perturbances as discussed here :
' Melatonin has both local and systemic effects after synthesis and is transferred into the bloodstream or gut lumen. Melatonin also has a considerable effect on the intestinal microbiota, which provides the gut's barrier integrity by reducing inflammation and oxidative stress. It also boosts the amount of intestinal microbiota by affecting their metabolism. Additionally, by controlling the metabolism of tryptophan and serotonin, the gut microbiota can affect the production of melatonin. Accumulating evidence has shown that melatonin can modulate the composition and abundance of the gut bacterial population in normal conditions, increase the diversity and frequency of intestinal microbiota, decrease the frequency of Bacteroides, and increase the frequency of firmicutes. Melatonin also increases Akkermansia flora’s frequency. In the animal model of spinal cord injury (SCI), melatonin decreased the frequency of Clostridium and increase the a frequency of Lactobacillus, Streptococcus mucophaphagus, and Myxobacter. When dysbiosis occurs, the permeability of the intestinal barrier increases, resulting in damage to the mucus and intestinal epithelial cells. As a result, large undesirable molecules and commensal bacteria can enter the lamina propria . This leads to the activation of the immune system and the production of inflammatory cytokines such as interferons, interleukin IL-17, IL-1B, IL-6, IL-8, IL-12, and TNF-α. Additionally, there is an increase in calcium-dependent oxidative stress. Induction of indoleamine 2,3-dioxygenase (IDO) is a significant result of increased proinflammatory cytokines IL-1, IL-6, IL-18, and especially interferon-gamma (INF-γ). IDO induce producing several neuroregulatory compounds, including kynurenic acid (KYNA) and the excitotoxic quinolinic acid (QUIN), by diverting tryptophan away from the production of serotonin and melatonin and along the kynurenine pathway. Cytokines and other inflammatory factors, as well as bacterial metabolites, traverse the CNS through blood vessels and the enteric nervous system (ENS), or via the afferent fibers of the vagus nerve, thereby disrupting the integrity of the blood-brain barrier (BBB). The BBB, a natural protective membrane, regulates the transportation of molecules and cells, thereby safeguarding the brain’s well-being. Therefore, BBB disruption can lead to neuroinflammation, which in turn has the potential to exacerbate neurological disorders. Among the metabolites that change due to dysbiosis are the levels of serotonin and melatonin, which decrease simultaneously. These changes are related to variations in neural activity, interregional patterning and mitochondrial function control because melatonin has antioxidant and neuroprotective effects, and prevents mitochondrial destruction. Changes in neuro-immuno-endocrine function are significantly influenced by the equilibrium between the control of the kynurenine and serotonin/melatonin arms of tryptophan metabolism. On the other hand, some hormones can affect the cytokines effects. Melatonin can reduce the production and effects of pro-inflammatory cytokines .
Given the gut activities of melatonin mentioned in the above quote, combined with the known effects of melatonin in the brain and rest of the body, as well as melatonin's protective role in mitochondria, it becomes clearer how and why melatonin should be very useful for slowing the disease process.
My opinion is that the combination of earlier morning and later afternoon sun exposure, melatonin lotion and oral melatonin should be more optimal for slowing the disease process, especially at earlier stages of the disease.
I can wholeheartedly endorse that last remark: "My opinion is that the combination of earlier morning and later afternoon sun exposure, melatonin lotion, and oral melatonin should be more optimal for slowing the disease process, especially in the earlier stages of the disease!”
Unfortunately, only the abstract of the mentioned study on melatonin deficiency in PWP is available (for free), but do you know to what extent there is an average deficiency?
Here is a relevant quote from the review article :
' Patients with PD had blunted circadian rhythms of melatonin secretion, and both the amplitude of the melatonin rhythm and the 24-h area-under-the-curve for circulating melatonin levels were significantly lower in PD participants, which indicated that circadian dysfunction may underlie excessive daytime sleepiness in PD (Videnovic et al., 2014). '
Here is a link to the original study that the above quote was taken from :
It is worth noting that reduced melatonin levels occur in many age related diseases of which PD is one. Also interesting that melatonin is often beneficial in many of these age related diseases.
The article is essentially discussing how circadian rhythms are disturbed and dysfunctional in neurodegenerative conditions such as PD and they further discuss how this may account for the sleep problems associated with PD as well as other neurodegenerative diseases such as AD.
This is a brief description of what circadian rhythms are and do :
' Circadian rhythms are the physical, mental, and behavioral changes an organism experiences over a 24-hour cycle. Light and dark have the biggest influence on circadian rhythms, but food intake, stress, physical activity, social environment, and temperature also affect them. Most living things have circadian rhythms, including animals, plants, and microorganisms. In humans, nearly every tissue and organ has its own circadian rhythm, and collectively they are tuned to the daily cycle of day and night. '
So the abstract goes on to say the following which is straight forward and fairly easy to understand:
' Circadian rhythms are physiological and behavioural cycles generated by an endogenous biological clock, the suprachiasmatic nucleus. The circadian system influences the majority of physiological processes, including sleep–wake homeostasis. Impaired sleep and alertness are common symptoms of neurodegenerative disorders, and circadian dysfunction might exacerbate the disease process. The pathophysiology of sleep–wake disturbances in these disorders remains largely unknown, and is presumably multifactorial. Circadian rhythm dysfunction is often observed in patients with Alzheimer disease, in whom it has a major impact on quality of life and represents one of the most important factors leading to institutionalization of patients. Similarly, sleep and circadian problems represent common nonmotor features of Parkinson disease and Huntington disease. Clinical studies and experiments in animal models of neurodegenerative disorders have revealed the progressive nature of circadian dysfunction throughout the course of neurodegeneration, and suggest strategies for the restoration of circadian rhythmicity involving behavioural and pharmacological interventions that target the sleep–wake cycle. In this Review, we discuss the role of the circadian system in the regulation of the sleep–wake cycle, and outline the implications of disrupted circadian timekeeping in neurodegenerative diseases. '
There is some, but not complete, understanding of ways to try and resync circadian rhythms in people. Eating our meals at the same time has shown benefit. Reducing certain stimulants such as caffeine, nicotine and alcohol. Keeping a regular sleeping schedule and preferably without naps during the day and especially afternoon naps. Exposure to earlier morning sun. Avoidance of bright light at night. Taking melatonin in the evening as day turns to night has shown some benefit in circadian rhythm restoration among other benefits. Regular exercise is also helpful in trying to restore circadian rhythm synchronicity.
This second to last item is one of the reasons I have discussed what I refer to as melatonin 123. This involves taking melatonin three times before going to bed.
As an example, if you want to go to bed at 11: 00 pm and you normally take 10 mg of melatonin at bed time, you would take 3 mg at 9:00 pm, 3 mg at 10:00 pm and 3 mg at 11:00 pm. The purpose of doing this is to try and replicate melatonin release by the pineal gland as day turns to night.. I have found this melatonin 123 to be more effective than just taking 10 mg of melatonin at bedtime to try and improve sleep. The pineal gland is reactive to the gradual loss of light as the day turns to night via signaling from the vision system, but bright light at night can have a negative impact on melatonin release from the pineal gland. Constant brighter light at night can disrupt some of the circadian rhythms.
One of the obvious symptoms of circadian rhythm disruption is poor sleep, but it also has a negative impact on disease states such as PD. All of the negative effects of circadian disruption have not been fully elucidated yet, but it is not a good thing for humans, animals and plants.
This is as simple as I am able to explain what is a fairly complex subject, but I hope I helped you to have a better understanding.
Super helpful! THANK YOU, especially for the 123 part and the part about the pineal gland. I also agree very much with something I saw you say earlier that probably serotonin is a part of this as well.
Melatonin is well established to dissolve in ethanol, hence the use of gin over various alcohols. It will also dissolve in vodka, but from feedback from friends it requires more vodka to fully dissolve the melatonin powder, resulting in a waterier end lotion.
I didn't test coconut oil because some people don't like the smell of it and the Cetaphil has very little smell to it and it has been around for ages. I don't know if the coconut oil will work alongside the gin, but I think most lotions will work.
Interesting how there was not a note mentioning whether or not those tested were on carbidopa/levodopa as my guess would be that the majority of them were and is the root cause in most PWP with sleep isues. Imo
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