Name: Folic acid, Vitamin B9
Goes well with: Vitamin B6, Vitamin B12
Number of scientific references: 55
Level of Evidence: Level II What is this?
Note: Levodopa treatment, the presence of certain gene mutations (MTHFR) and possibly some other factors lower folate levels in Parkinson’s disease patients. This leads to increase in levels of amino acid homocysteine which adversely affects the heart and vascular health. Folic acid supplementation with vitamin B12 lowers homocysteine levels and reduces risk of stroke in PD patients.
The discussion of utility and benefits of folic acid for any disease is incomplete without the mention of methylation process. Epigenetics is a biological mechanism which alters gene activity without actually changing the DNA sequence of the gene. And methylation is one of the many epigenetic processes.
DNA methylation involves the addition of the methyl group to the DNA and this addiction impacts the gene function. Fine tuning or controlling the DNA methylation process can help regulate gene expression or switch genes on or off.
Alterations in various genes such as PARK1-15, LRRK2, MAPT, GPNMB have been associated with Parkinson’s disease risk. Mutations in SNCA gene leads to abnormal accumulation of alpha-synuclein protein in the brain. These aggregates are called Lewy bodies, and they contribute to the development of PD.
Apart from SNCA mutation, its amplification or overexpression may also lead to the formation of Lewy bodies. DNA methylation is a potential mechanism for controlling SNCA gene’s activity. Most studies suggest that hypomethylation or reduced methylation leads to an increase in SNCA activity; but there a few exceptions to this.
Apart from SNCA gene, the methylation status of many other genes has been associated with PD risk. There is still conflicting evidence available on the involvement of DNA methylation in regulating major PD associated genes.
But further research can help identify the missing link between environmental factors and genetic risks of PD and also help us understand how nutrition can impact DNA methylation in PD.
Folic acid deficiency affects the methylation status by regulating biochemical pathways linked with it.
The folic acid supplement can help in Parkinson’s disease by lowering levels of amino acid homocysteine and protecting the heart and vascular health in PD patients. PD patients have high homocysteine levels as a result of folic acid deficiency and levodopa treatment.
But before we get to the benefits of folic acid in Parkinson’s, let’s understand the effect of genes that regulate methylation status in the disease.
How does MTHFR mutation impact symptoms of Parkinson’s disease?
DNA methylation is possibly linked to folate levels. One carbon pathway is a biochemical pathway that converts folate in the diet to other essential biological agents.
Table of Contents
- 1 How does MTHFR mutation impact symptoms of Parkinson’s disease?
- 2 Suggested Folic Acid/Folate Supplements For Parkinson’s Disease
- 3 4 Potential Ways Folic Acid Helps In Parkinson’s Disease
- 4 Dosage of Folic Acid For Parkinson’s Disease
- 5 Precautions with Folic Acid Use
- 6 Conclusion
MTHFR or methylene-tetra-hydro-folate reductase gene is a gene that codes for the MTHFR enzyme and this enzyme are essential for supporting folate metabolism via the one-carbon pathway.
It converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, and this product is required for conversion of homocysteine to methionine (an amino acid).
Variants in MTHFR gene lead to reduced enzymatic activity and increased homocysteine levels.
Two variations have been studied in this gene (these are changes or replacement in nitrogenous bases in genes which is different from what normal individuals have):
• A to C change at position 1298
• C to T change at position 677
Further, there are other subtypes in MTHFR C677T gene variant:
• CC genotype: normal
• CT genotype: heterozygous type with a single copy
• TT genotype: homozygous type with two copies
The presence of MTHFRC677T gene mutation has been associated with increased risk of Parkinson’s disease. A few inconsistent findings can be attributed to differences caused by genetic background or environmental factors.
Elevated homocysteine levels affect vascular health and are toxic to the dopaminergic neurons. (These are brain cells that affect motor function in PD.) To reduce the homocysteine levels, folate supplementation is necessary.
High homocysteine levels are a sign of folate deficiency. Folate deficiency can have neurological symptoms such as neuropathy, depression, dementia and cognitive impairment.
These symptoms can overlap with symptoms of vitamin B12 deficiency. Thus it is important to balance both folate and vitamin B12 levels for healthy nervous system function.
Now let’s go over the various studies that have explored the benefits of folic acid in Parkinson’s disease.
Suggested Folic Acid/Folate Supplements For Parkinson’s Disease
Please consult a health practitioner before taking any health supplements.
If you have been tested positive for MTHFR mutation and have been diagnosed with early Parkinson’s, then it is advised to supplement with folate as well other B vitamins.
If you are aiming to manage high homocysteine levels in mid-stage Parkinson’s disease please discuss the safety and dosage of folic acid/folate with your doctor.
This is one supplement that I came across that helps support methylation status and is reported to be beneficial for MTHFR mutation by users.
|Thorne Research Methyl-Guard Plus|
|This supplement contains folate, vitamin B6, riboflavin, vitamin B12 and betaine packed in veg capsules.
Dosage: 1-2 capsules per day or follow manufacturer’s recommended dosage
Image Credit: Thorne Research, Inc.
Individual Folic Acid Supplements
If you are looking for individual supplements then here are a few suggested folic acid and folate supplements. You may even consider taking a complete B-complex supplement (Buy from Amazon or iHerb) in addition to this (only in case of deficiency).
Dosage: 1-5 mg. Please confirm dosage with your doctor.
|Solgar Folic Acid 800mcg capsules||Thorne Research-5-MTHF- 1mg Folate|
Image Credit: Solgar Inc.
Image Credit: Thorne Research, Inc.
|Contains 800mcg folic acid in veg capsules||Contains 1 mg 5-MTHF or folate per veg capsule|
4 Potential Ways Folic Acid Helps In Parkinson’s Disease
Here are few ways by which folic acid supplementation may benefit in Parkinson’s disease.
1.Folic acid supplementation may protect Parkinson’s patients from hyperhomocysteinemia
Homocysteine is an amino acid, and it’s a by-product of the one-carbon pathway. It can be recycled to methionine (an amino acid) or converted to cysteine with the help of vitamins such as folate and vitamin B6.
High homocysteine levels are referred to as hyperhomocysteinemia. High levels of homocysteine can cause blood clots and affect vascular health.
Levodopa treatment in Parkinson’s can cause high levels of homocysteine. If you are wondering how this occurs, then here is the gist of what happens on a molecular level.
Levodopa is administered with dopa decarboxylase inhibitors (DDIs) to prevent levodopa from breaking down before reaching the brain tissue. This increases the concentration of levodopa as well its susceptibility to breakdown by an enzyme catechol-O-methyltransferase (COMT).
COMT requires magnesium ion and SAMe (S-adenosyl methionine) to function. SAMe helps COMT to provide methyl group to levodopa and converts it to 3-O-methyldopa. At the same time, SAMe gets converted to S-adenosylhomocysteine and subsequently to homocysteine.
Thus, PD patients treated with levodopa have reduced SAMe levels and high homocysteine levels. This could contribute to depression and heart risks in PD.
To avoid this COMT inhibitor are developed to inhibit breakdown by COMT and is administered in combination with levodopa and DDIs. COMT inhibitors should reduce homocysteine levels in PD patients theoretically.
However, a recent study published in Biomed Research International, 2016 reported that COMT inhibitors might not be not sufficient in reducing homocysteine levels.
Researchers from Montreal General Hospital, Canada found that a six week therapy of folic acid and vitamin B12 was more efficient in reducing homocysteine levels in PD patients than a COMT inhibitor.
One reason for the lack of effectiveness of COMT inhibitors is that PD patients could be deficient in vitamins and minerals such vitamin B12 and folic acid.
A study published in European Neurology, 2007 reported that patients treated with levodopa have lower vitamin B12 and folate levels. And the addition of COMT inhibitor reduces the levels even further.
Individuals homozygous for the gene (TT677 genotype) are reported to have the highest homocysteine levels, and this leads to oxidative stress in PD (Neuromolecular Medicine, 2007).
Researchers have demonstrated that folic acid deficiency is one of the core factors responsible for hyperhomocysteinemia in PD. They suggest that supplementation with folic acid and vitamin B12 may lower not only homocysteine levels but also reduce motor and cognitive symptoms.
Lamberti and colleagues have successfully shown that supplementation with vitamin B12 and folate can effectively reduce homocysteine levels that were elevated by levodopa treatment.
Another similar study was published in European Review For Medical and Pharmacological Sciences, 2016. 93 patients that were newly diagnosed with PD were enrolled in the study.
They were assigned to two groups; one received levodopa and DDI treatment while the other was not treated with levodopa and DDI.
At the first visit patients receiving levodopa and DDI treatment had significantly higher homocysteine levels than the patients who did not receive treatment. But after five months both groups presented with high homocysteine levels.
(This indicates that rise in homocysteine levels can’t be attributed to levodopa alone; folate and vitamin B deficiency could also be important determinants.)
After 5 months patients with high homocysteine levels were allotted to two groups:
- Treatment group: 500 microgram methylcobalamin and 5mg folic acid once a day
- Control group
Both groups received levodopa and DDI treatment.
Three-month therapy with folic acid and B vitamins reduced homocysteine levels in treatment group only. No patients treated with vitamins experienced a stroke and only four patients presented with increased stroke risk.
However, in the control group, two patients experienced an ischemic stroke, and 11 patients showed increased stroke risk.
The researchers concluded that supplementation with methylcobalamin and folic acid could reduce homocysteine levels and reduce the risk of developing a stroke in PD patients.
Quick Gist: Levodopa treatment, the presence of MTHFR mutation and folic acid deficiency can increase homocysteine levels in PD patients. High homocysteine levels increase the risk of developing heart diseases, cerebral strokes and can impair cognition.
Supplementation with folic acid and vitamin B12 can effectively reduce homocysteine levels and protect heart health in PD.
2.Pre-clinical studies show that dietary folate has an anti-Parkinsonian effect
Mitochondria are energy-producing units of the cell. Mitochondrial dysfunction and oxidative stress contribute to pathological processes of Parkinson’s disease.
Genetic mutations associated with Parkinson’s disease can cause mitochondrial dysfunction. PINK1 gene is a gene that keeps a check on the quality control and function of mitochondria. PINK1 gene mutations cause autosomal recessive and early-onset Parkinson’s disease (PD).
In a fly model of Parkinson’s, dietary supplementation with folinic acid (folate) is proven to prevent brain cell degeneration in PINK1 mutants by possibly rectifying defects in the mitochondria.
Folic acid protects brain cells that utilise neurotransmitters dopamine and serotonin, restore mitochondrial function and reduce oxidative stress. The combination of these pharmacological effects is found to reduce motor symptoms of PD in experimental models.
Folate and folic acid supplementation can also lower homocysteine levels and thus protect dopaminergic neurons from its toxic effect. Protection of dopaminergic neurons in certain areas of the brain can ameliorate motor impairment in PD.
Also, observational studies have reported that low levels of folate intake may not be associated with increased risk of Parkinson’s. Some studies have found that dietary vitamin B6 may decrease the risk of PD.
In contrast, findings of a recent study highlight that low levels of vitamin B1 and folate in diet, 2-8 years before PD diagnosis, is strongly associated with a disturbed sense of smell at the time of diagnosis.
Further research is required to address these discrepancies taking into account the effect of certain genetic mutations that impair folate metabolism.
Quick Gist: Pre-clinical studies have shown that folic acid or dietary folate supplementation can help prevent brain cell degeneration even when one expresses genetic mutations that are associated with Parkinson’s disease. This observation is still to be confirmed by human studies.
3.Folic acid can reduce neuropathy symptoms
B complex vitamins help in peripheral neuropathy by protecting nerve health and supporting nerve regeneration.
Treatment with uridine monophosphate (nucleotides), folic acid and vitamin B12 (this proprietary blend is known as Keltican) is found to halt the progression of peripheral neuropathy.
The clinical study published in Pain Management, 2014 demonstrated that treatment with folate, B12 and uridine monophosphate reduced neuropathic pain significantly. 77.4% patients reduced or withdrew the use of nonsteroidal anti-inflammatory drugs.
Quick Gist: Folic acid supplementation, in combination with vitamin B12, can help protect from peripheral neuropathy in PD by reducing vitamin deficiency, supporting nerve regeneration and relieving neuropathic pain.
4.It may protect cognition
Methylation status is found to be associated with cognitive function in PD; higher methylation status better cognition. Individuals with cognitive impairment in PD are found to have higher homocysteine levels.
Some studies have found no association between MTHFR mutation or high homocysteine levels with cognition in PD and this could be attributed to a variety of other factors and the heterogeneous nature of the disease.
However, a recent review study published in Neuroscience Letters, 2017 reported that patients with cognitive impairment in PD are likely to have high homocysteine levels, lower folate and vitamin B12 levels.
Low folate levels in PD may be associated with depression while low B12 levels may be linked with cognitive impairment.
Review studies suggest that folic acid and vitamin B12 do not have a significant benefit for cognition, but they are effective in reducing homocysteine levels. High homocysteine levels are toxic to brain cells.
Quick Gist: Folic and vitamin B12 supplementation may help protect cognition in PD by lowering homocysteine levels. Further research regarding clinical trials is required to confirm this.
Dosage of Folic Acid For Parkinson’s Disease
No specific guidelines have been outlined for the dosage of folic acid for Parkinson’s. Studies in humans have used a dose range of 1-5mg folic acid per day in combination with other B vitamins (vitamin B6 and B12).
It is important to consult your health practitioner before taking folic acid supplements when you are already taking medications for Parkinson’s. The dosage recommendations may differ for every individual.
Also, if you have tested positive for the MTHFR mutation, please speak to your doctor about folate and other methylated B vitamin supplementation.
Maintain a 2-3 hour gap between taking B vitamins and PD medications.
Precautions with Folic Acid Use
Side effects of dietary folic acid are rare. Very high dose of folic acid may cause side effects like:
- Loss of appetite
- Stomach issues
- Sleep disturbances
- Confusion or reduction in mental function
- Kidney damage
- Allergic reaction
Folic acid tends to hide symptoms of vitamin B12 deficiency or anaemia. So if you have been diagnosed with either of these, you should consult a health practitioner before taking folic acid.
Individuals being treated for cancer or seizures should consult a health practitioner before taking folic acid supplements.
Folic acid may interact with certain medications: oral contraceptives, antibiotics, anti-seizure medicines, chemotherapeutic agents, pyrimethamine, pentamidine, trimethoprim, triamterene and certain medications that lower folic acid levels. Please check the full list noted by UMM.
Folic acid, as well as other B vitamins, are essential for healthy functioning of the nervous system. Preclinical studies and theoretical evidence highlight the various ways by which folic acid can benefit in Parkinson’s: reducing motor symptoms and exerting an anti-Parkinsonian effect, preventing cognitive impairment and reducing the risk of PD.
But these findings are yet to be proven in human studies.
Levodopa treatment can increase homocysteine levels in PD patients. MTHFR mutation and coexisting folate deficiency may contribute to the rise in homocysteine levels, and this can hurt heart and vascular health of PD patients.
Folic acid supplementation, in combination with vitamin B12, is proven to reduce homocysteine levels in PD patients being treated with levodopa and is found to reduce the risk of stroke in patients.
It is advisable to discuss the benefits of folic acid supplementation with your doctor if you are receiving levodopa treatment and also if you have MTHFR mutation.
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