Long story short: About 20% of PwP have abnormally high homocysteine. And even when it is not abnormally high, it is still higher than non PwP. There does not seem to be a correlation between homocysteine levels and severity and duration of PD, but homocysteine is known to be toxic to neurons. ncbi.nlm.nih.gov/labs/pmc/a...
I found this study where they used Folic Acid to normalize homocysteine in PwP: HYPERHOMOCYSTEINEMIA AND ITS TREATMENT IN PATIENTS WITH PARKINSON’S DISEASE 2016 ncbi.nlm.nih.gov/labs/pmc/a...
Materials and Methods:
We measured levels of homocysteine in thirty patients (15::15) with “de novo” Parkinson’s disease, with average age 64.17 ± 13.19 (28-82) years (Department of Neurology, University Clinical Center Tuzla). Normal level of homocysteine for women was 3.36-20.44 micromole/l and 5.9-16 micromole/l for men. We followed the effects of medicament approach (folic acid) every six months for next five years.
Results:
20% of patients with “de novo” Parkinson’s disease exhibited hyperhomocysteinemia. An average level of homocysteine was 13.85 ± 5.82 micromole/l. Differences due to age and homocysteine levels, regardless of sex, were not concluded. For the next five years intake of folic acid (periodically, 1-2 months, 5 mg per day, orally) was effective to normalized levels of homocysteine in all.
Conclusion:
Hyperhomocysteinemia is present in every fifth patient with “de novo” Parkinson’s disease. Folic acid is medication of choice in treatment of hyperhomocysteinemia coexisting with Parkinson’s disease.
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I want to add that apparently you can't just take folic acid long term. You need breaks. There is more in the article. This was interesting also:
"Folates could protect blood vessels and prevent DNA damage caused by oxidative stress (3,4). However, research undertaken on embryonic cortical neuron’s culture and human neuroblasts has shown that in the median there is an increase in products of oxidation and apoptosis without the presence of folate. Outcomes of some studies have indicated that the values of vitamin B12 and folic acid are in negative correlation with hyperhomocysteinemia of patients with PD (20). Vitamins B2, B6, B12 have antiatherogenic effect by reducing homocysteine level. It seems that diet approach and an increase of folic acid level, due to the effect on homocysteine metabolism, should have a positive influence on the fast aging process and degenerative diseases. It is considered that sole increased intake of B-vitamins also lowers the possibility of PD development by some mechanisms that are not utterly linked with the metabolism of homocysteine (21)."
Homocysteine is an essential intermediate product of biochemical reactions that is present in various tissues of the human body. Homocysteine may be associated with the development and progression of Parkinson’s disease. Plasma homocysteine levels in patients with Parkinson’s disease are elevated compared to those of healthy individuals. High homocysteine drives PD development and progression while aggregating the clinical symptoms of PD patients. The relationship between PD and homocysteine involves multiple pathways, including nerve cell apoptosis, oxidative stress, and DNA damage. This is crucial for explaining how high homocysteine drives the PD procession. Elevated homocysteine level during PD development and progression offers a new strategy for the diagnosis and treatment of this disease."
"The Hcy produced in the human body is mainly eliminated through the following three metabolic pathways. (1) Remethylation: Hcy is remethylated to methionine by 5,10-methylenetetrahydrofolate reductase and methionine synthetase, with vitamins B2 and B12 as cofactors.11 (2) Transsulfuration, namely, the condensation of Hcy with serine: Hcy is first transformed into cystathionine, in which cystathionine β-synthase must be liberated and vitamin B6 is used as a cofactor; further, the cystathionine produced is metabolized into cysteine and α-ketobutyric acid which are excreted from the body.12 (3) Release into the extracellular fluid, which is indicative of the balance between Hcy production and metabolism: at low concentrations of methionine, the cellular release of Hcy is mainly controlled by the activity of methionine synthase, while at high concentrations of methionine, cystathionine synthetase activity primarily determines Hcy release.13 Studies have shown that high concentrations of Hcy are closely linked to PD development and progression, and Hcy may become a feasible therapeutic target for cognitive decline in PD.14 Therefore, understanding the role of Hcy in PD development and progression is of great significance to revealing the pathogenesis of the disease."
"A nutritional status analysis has revealed that folic acid, vitamin B12, and vitamin B6 are closely associated with Hcy metabolism; any nutritional deficiencies that could lead to a decrease in folic acid, vitamin B12, or vitamin B6 concentration would increase the risk of Hhcy.22 Reportedly, ~2/3 of Hhcy cases are caused by deficient blood concentrations of two or more vitamin cofactors.22"
"Elevations of Homocysteine Levels in Parkinson’s Disease
Epidemiological and clinical studies have shown that the elevation of plasma Hcy levels is a high-risk factor for neurodegenerative diseases.34 Kuhn et al.35 reported that the plasma Hcy levels in PD patients were substantially higher than in the control group. High Hcy-induced loss of intracellular ATP was suggested to be a crucial factor leading to PD.36 Duan et al.37 noted that Hhcy contributed to the decrease in dopaminergic neurons in a rat PD model, while it enhanced the sensitivity of human dopaminergic neurons to rotenone and iron ions in vitro; these results suggest that Hhcy can destroy dopaminergic neurons through increasing their sensitivity to toxins, thereby driving the pathogenesis of PD and accelerating disease progression. O'Suilleabhain et al.38 found that PD patients with elevated plasma Hcy levels were more depressed and cognitively impaired than the patients with nonelevated Hcy levels. Because an elevated Hcy level can usually be lowered by vitamin supplementation, these findings have potential therapeutic implications for ameliorating rates of clinical deterioration.38"
"Conclusion
Plasma Hcy concentrations are increased in patients with PD compared to healthy individuals. Hhcy drives PD development and progression while aggregating the clinical symptoms among PD patients. Thus, Hhcy may be a risk factor of PD. The relationship between PD and Hcy involves multiple pathways, including gene defects, apoptosis, oxidative stress, and DNA damage. Therefore, the detection and intervention of plasma Hcy levels in patients with PD can facilitate the retardation and control of PD progression, which has implications for improving the prognosis and the quality of life of the patients."
If you are going to use folic acid as a means to lower homocysteine, it might be a better choice to use folate instead. park_bear has written extensively on the use of Folic Acid and apparently there is at least one risk involved in its use. On a related note, melatonin is also noted for lowering homocysteine levels and it comes with many other potential health benefits.
So this article is about homocysteine and cardio vascular disease. It says you can lower your homocysteine with supplements but that won't affect your risk of CVD: pubmed.ncbi.nlm.nih.gov/176...
On a related note, melatonin lowers homocysteine and is very effective as a preventative or treatment for CVD, which PwP are at increased risk for. The risk that park_bear mentioned with folic acid use is cancer.
Thanks Art. I recall that they put folic acid in all sorts of foods to help prevent birth defects in pregnant women, but that it doubles the chances of colon cancer in everybody else. Follow the money!
Art, JAMA has a recent 2022 article stating that melatonin used for long periods can cause dementia. I read a summary of the study but did not have access to the actual study. Have you read it? I’m concerned though. Melatonin increases GABA and PWP should exercise extreme caution with increasing GABA.
Melatonin levels in the serum and cerebrospinal fluid (CSF) are lower in AD patients than those in age-matched control subjects [48,49,50].Moreover, melatonin supplementation was shown to alleviate the dysregulation of the circadian rhythm and improve cognition in AD patients [51,52].
>>> ' The pineal hormone melatonin has already applied in clinical practice. Melatonin could protect neurons from Aβo-induced neurotoxicity and regulate Aβ production/clearance balance in the brains of AD. Therefore, continuous melatonin supplementation may help prevent neurodegeneration and Aβ accumulation in aged people. Since melatonin has low toxicity and high efficacy in many pathophysiological states, it might be a promising and safe anti-amyloid agent against AD. ' <<<
>>> ' Meta-analysis of MMSE score suggested that melatonin is effective in treatment for mild stage of AD. Additionally, we propose that melatonin may be preferable to traditional hypnotics in management of insomnia. " <<<
Considering that AB is also an issue in PD, the ability of melatonin to regulate AB production, clear and protect neurons from AB neurotoxicity seems relevant for PD also.
Agreed Art. My first reply was just what I found Googling "JAMA Melatonin Dementia". All I found was some news pages and they were super vague. Most of what I find says Melatonin helps.
Neurocognitive effects of melatonin treatment in healthy adults and individuals with Alzheimer’s disease and insomnia: A systematic review and meta-analysis of randomized controlled trials 2021 sciencedirect.com/science/a...
"5. Conclusion
The available evidence suggests that melatonin treatment for > 12 weeks may be effective for improvement of cognitive functioning in AD. In particular, patients with mild AD may show greater beneficial effects of melatonin intervention than those with moderate AD. This will be valuable for caregivers to decrease the burden of AD. Although daytime melatonin administration produced a significant reduction of accuracy, the other cognitive subdomains, such as reaction time and memory, remained unchanged by melatonin treatment. Therefore, we propose that melatonin may be preferable to traditional hypnotics, such as benzodiazepines, in the management of circadian disruption and insomnia. Finally, before melatonin intervention can be recommended for the improvement of cognition, as adjuvant AD therapy or as an alternative of traditional hypnotics, further high-quality studies with larger sample sizes and longer duration are needed."
I have not found a long term outcome study though, have you? This concern is all brought about by my realization of glutamate excitoxicity and GABA astrocytes.
I searched for, "melatonin dementia 2022 JAMA" and got no results that were relevant except this article which is similar to the article that Bolt referenced :
In this article, this is an exact quote and it should be noted that they incorrectly referred to the NIH as the National Institutes for Health. The word "for" should be "of". :
>>> ' The National Institutes for Health said using melatonin occasionally is fine but high levels have been linked to dementia, early mortality and other health issues. '<<<
When you follow the link to the NIH reference that they are supposedly getting the information from, that page only talks about general information about melatonin and makes zero mention of the claim made by the article. Here is the link given by the article :
The claim made by this article is not substantiated by studies of recent years and the page they link to, to corroborate the claim they are making, does not support their claim. You can take from the article what you want, but based on studies, the claim seems to be lacking in corroborating evidence and contradictory to recent studies that are easily found as I linked to three studies earlier in this thread that state essentially the opposite.
I was researching melatonin as it relates to GABA bc I’m concerned about supplementing with an over balance of things that turn in to glutamate bc of glutamate excitoxicity. That lead me to the JAMA page which I could not open. So I found that poorly done article summarizing it.
Melatonin increases gaba so does that cause an increase in glutamate worsening the long term over abundance of both GABA astrocytes and glutamate Excitotoxicity?
This is a very valid and important concern.
Rescuema can explain the process better than me of course.
Melatonin is complex far beyond its antioxidant abilities. It increases GABA. GABA converts to glutamate. Glutamate Excitotoxicity? That is what led me down this rabbit hole. I do not doubt it’s positive effects but what additional effects are there?
Too much of a good thing is a bad thing. Didn't know it converts to GABA. *I was prescribed Gabapentin about a year before my formal dx. I couldn't find info on efficacy or contraindications so I didn't take it. Found a YouTube video of a woman who got tardive dyskinesia from gabapentin and wanted to warn others. A friend of a friend had ALS, dead within 6 months after taking gabapentin. Can't be too careful.
Your story exemplifies my concern! GABA increasing meds and supplements definitely confer short term benefits but what is the long term consequence? Are GABA agonists improving our symptoms and speeding our decline? Studies done on deceased PWP showed that PWP have GABA astrocytes basically forcing the neurons in to a zombie state. Who can help me determine this? Why is this not discussed?
Gabapentin was designed to mimic the neurotransmitter GABA. It does not, however, bind to GABA receptors.
[Research has shown that gabapentin exerts a modulating effect at neuronal receptor sites, inhibiting the release of the neurotransmitters dopamine, serotonin and norepinephrine and resulting in increased GABA concentrations in various locations throughout the brain.]
Management of Restless Leg Syndrome with Gabapentin
>>> ' The results suggest that simultaneous melatonin treatment significantly attenuated the NMDA receptor mediated glutamate excitotoxicity and protects the inhibition of BDNF signaling caused by PCBs exposure in cerebral cortex of adult male rats. ' <<<
It is only a rat study, but given the type of testing required to do such a study on what is going on inside the brain, a similar study in humans does not seem possible with current science.
Thank you. A glimmer of relief as this is so important! Only a rat study to explain this very important subject is disappointing. I don’t understand how it “compensates for glutamate Excitotoxicity” but it’s a start. Thank you
A human study that comes to mind is a melatonin / ALS study that used high dose (300 mg/day delivered rectally) melatonin for up to two years in ALS patients.
Importantly, aside from returning oxidative stress markers to the levels of healthy controls, melatonin did the following in cultured motoneurons :
>>> ' We found that melatonin attenuates glutamate-induced cell death of cultured motoneurons. ' <<<
>>> ' In a clinical safety study, chronic high-dose (300 mg/day) rectal melatonin was well tolerated during an observation period of up to 2 yr. Importantly, circulating serum protein carbonyls, which provide a surrogate marker for oxidative stress, were elevated in ALS patients, but were normalized to control values by melatonin treatment. This combination of preclinical effectiveness and proven safety in humans suggests that high-dose melatonin is suitable for clinical trials aimed at neuroprotection through antioxidation in ALS. ' <<<
In the mice portion of this study, melatonin delayed disease progression and extended survival.
It is important to note that rectal delivery is likely to have higher bioavailability than oral delivery which is estimated to be in the 3% to 15% range, so the 300 mg delivered rectally is important.
As I mentioned in a previous reply, this is about as close as you are going to get to an actual human study where the brain would have to be analyzed in detail, which is currently not possible in a living person.
The sad part of that first study was that they did not do a follow up study to add more information to their findings. For a disease like ALS with limited treatment options, it would seem appropriate to do confirmatory studies. That study was completed in 2006.
Can you link to this study using 1500 mg rectally in cancer patients? I have never seen this study and would like to see it as it is one of the highest doses I have ever seen used of melatonin in people with cancer.
you are the melatonin expert on here. Melatonin is a GAMA agonist. As I stated a few other places, this matter bc GABA astrocytes literally cause dopamine zombie neurons. Does melatonin, especially at high doses worsen this?
I think it’s pretty urgent we determine this before continuing with high doses of melatonin.
This is not the best paper on this but it’s what I have at the moment. Rescuema can direct us to better.
There has been over 4,000 publications in peer review journals in the National Library of Medicine confirming melatonin, in super high physiologic dosages is safe and not toxic with dosages as high as 52,000 mg in animal models showing no toxicity. It has been shown in these studies to be the most powerful antioxidant our bodies use!
This video by Dr. Reiter is an excellent place to start with your own journey to discover melatonin and how it may help you.
I will listen today. I don’t doubt it’s the most powerful antioxidant. I am concerned about what else it is doing. It is a complex hormone. How does it affect GABA and how does that affect the long term prognosis of the PD and ALS brain?
Isn't melatonin a hormone? I know the body produces it, but as a master antioxidant I have not read this. Not that I've read about melatonin either ...just enquiring
Melatonin is a neurohormone, it isn't an antioxidant, it's a free radical scavenger. Acting as a prohormone, melatonin supports the production of antioxidants like glutathione and superoxidase dismutase.
Ppl with neurodegenerative conditions need extra melatonin and zinc supplement (with trace amounts of copper).
Melatonin reduces oxidative stress even more than vitamin D. But, I’m concerned that very high doses create the problem of excess GABA which in turn increases glutamate. An example of this is that it can cause insomnia if too high a dose is used. GABA does not cause insomnia, to the contrary. Glutamate does. I’m still taking 20 mg but I was taking 30.
I’m tapering down to 15 mg
For zinc and copper, do you have a preferred type or source?
I am late to the party (and not scientifically trained or learned) but recall that in 2018 at a clinic in Denver CO my bloods revealed an homocysteine reading of 14.30. I was told it was high and that the optimal range was 0.00-7.20 and the standard range 0.00-10.30. [I notice that in the original post Bolt quoted an average of 13.85 and a normal range of 5.9-16 in men] I cant reconcile why on one basis my reading was high but on another normal!] But that may simply mean that I can ignore the perceived high reading as no one can say what is normal after all! On the basis that my reading was high - I was told that a raised level of homocysteine indicated incomplete breakdown of the amino acid methionine and a likely causation of that was “deficiency” in B6, B12 and Folate predisposing me to cardiovascular disease as well as my PD. I started off in good faith and took the recommended supplements, but as the years passed and the number of supplements became an avalanche with insufficient hours in the day to take them (or water to wash them down!), and a counter indication from my neurologist about B6, they gradually fell by the wayside. On one view that was serendipity - on another a mistake. My take from this discussion is - resume B12 (Thiamine?), be wary of Folate, can’t go far wrong with Melatonin and Magnesium if sleep is an issue (writing this at 0400), and probably increase Zinc (not raised here) and more Vit D (D3 is a favourite). Unless anyone is going to raise a posse to stop me, I’m putting them in my saddlebag and riding off into the sunset (back to bed). I do have to end by saying reading these exchanges gives me a daily boost (or perhaps keeps me awake at night!). Thanks everyone. I marvel at your knowledge and dedication and have no idea where you find the time!
MTHFR is an enzyme that breaks down homocysteine. Homocysteine is an amino acid that the body produces by breaking down dietary proteins.
Having high levels of homocysteine can damage blood vessels and lead to blood clots. People who have high homocysteine levels tend to have low levels of vitamin B12. People with high homocysteine levels due to folate (B9) or vitamin B12 deficiencies can take folic acid or vitamin B12, respectively.
You want methylated B12 (cobalamin) there are different forms and I recommend you take a combination of all of them.
Ditto with Magnesium, you want a combination of the forms.
Zinc supplementation needs to be accompanied by Copper, because zinc depletes this trace element.
I'm grateful to have a platform to share what I've learned and also learn from other research warriors ❤️❤️❤️
SE
*I've been researching/searching for answers about what caused my ALS, my mom's PD, my grandmother's dementia and some of my son's ASDs. I've been researching ways to slowdown/stop/reverse and prevent NDD. This epidemic stops with me. I'm disabled now and this has become my purpose.
Effects of folic acid plus levothyroxine on serum homocysteine level in hypothyroidism 2012 ncbi.nlm.nih.gov/labs/pmc/a...
Conclusion: Levothyroxine can decrease serum homocysteine level partly; still its combination with folic acid empowers the effect. Combination therapy declines serum homocysteine level more successfully.
"L-methylfolate is thought to be the only form of folate that is able to pass through the blood–brain barrier and is involved in the regeneration of tetrahydrobiopterin (BH4; a critical cofactor for neurotransmitter synthesis), the levels of which are depleted with inflammation or oxidative stress."
"Our results suggest that serum folate levels in the upper half of the distribution are associated with a moderately increased lung cancer risk among smokers from northern Poland. If so, relatively small differences in folate concentrations may support growth and progression of smoking induced lung cancer. We believe it would be interesting to repeat this study in other populations of smokers, with a strict matching of cases and controls for pack-years of cigarettes smoked, to test if the observed effect is general. Further, the female carriers of the SLC19A1 c.80A allele belong to the group exhibiting increased lung cancer incidence pointing that certain associations between the folate/homocysteine pathway and the development of smoking-related lung cancer are sex-specific."
Severe Hyperhomocysteinemia in a Patient with Parkinson Disease [2022]
"A woman in her sixties was admitted to the hospital after she had a generalized epileptic seizure. For the last 20 years, she had Parkinson disease. Her clinical history additionally included coronary heart disease, type 2 diabetes, and obesity.
Her Parkinsonian symptoms included postural instability, bladder dysfunction, rigidity, tremor, and dystonia in the neck and lower extremities. She had used Sinemet (carbidopa/levodopa) 25/100 mg 10 times daily for at least 10 years, in addition to tolcapone 100 mg 3 times daily and botulinum toxin for dystonia. During the previous 3 months before admittance to hospital, she had experienced increasing nausea, vomiting, dizziness and stomach pain, and reduced walking ability. In this period, she also had several serious infections and a weight loss of approximately 30 kg. ... "
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Diabetes and Parkinson's disease 
The more homocysteine, the worse the Parkinson's?
