People with Parkinson's disease (PwP) are at increased risk for getting Peripheral Neuropathy (PN). PN can have many causes.
Multiple causes other than PD such as diabetes, insulin resistance or certain chemotherapy agents can also cause PN. The main consideration is that the nerves are being damaged and this often manifests as pain, burning, tingling or numbness in the feet and or hands that can be overwhelming in terms of pain and downright dangerous in terms of numbness because you lose the nerve sensory input that helps you maintain your balance thus exposing you to the danger of falling.
' Peripheral neuropathy is a condition in which there is damage to the peripheral nervous system, the system of nerve fibers that innervates the organs and limbs.
Peripheral neuropathy may cause weakness, imbalance with walking, numbness, pain or paresthesias (abnormal sensation such as tingling or burning), usually in the feet (but sometimes in the hands as well).
There is a higher rate of peripheral neuropathy among people with PD as compared to those without PD, although the nature of this relationship is unclear.
Levodopa treatment may contribute to lower Vitamin B12 levels which may contribute to peripheral neuropathy. '
Vitamin B12
In PD, in particular, it is thought that one potential reason for PN is that Levodopa therapy may contribute to lower vitamin B12 levels and this may result in elevated homocysteine levels and this among other health negatives is thought to be a risk factor for PN. Vitamin B12 is considered as one of the treatments for PN based on available studies. PwP are also noted for having lower B12 levels so it seems like supplementing with a more bioavailable form of B12 is a good starting point.
' Vitamin B12 deficiency in humans is known to contribute to a variety of neurological conditions and low vitamin B12 levels have been described in patients with idiopathic PD. A recent study showed that low levels of vitamin B12 predict worse motor symptoms for patients early on in PD progression. '
Vitamin B1 As Benfotiamine
Vitamin B1 is also known to be beneficial for fighting PN, in the form of Benfotiamine at 600 mg per day in two divided doses of 300 mg with meals.
' Studies have shown that benfotiamine improves neuropathy scores significantly,301,302 increases nerve conduction velocity,303-305 and reduces HbA1c and pain.30 '
Vitamin B6 As P5P
Next in line is Vitamin B6 for PN, but B6 can be a double edged sword when it comes to PN because while the right level of B6 can help fight PN, too much B6 can promote PN as can too little and the damage that too much B6 can cause is considered irreversible in some people. So it is important to work with your doctor to make sure your B6 level is optimal.
' A known side effect of vitamin B6 is peripheral neuropathy, which has symptoms of tingling, burning or numbness, usually in the hands or feet. It usually occurs at high doses or following long-term use of products containing vitamin B6. Peripheral neuropathy is not associated with normal dietary intakes of vitamin B6.
So the bottom line for PwP with PN is to make sure your B1/Benfotiamine, B6/P5P and B12 levels are optimal.
R-Alpha Lipoic Acid
The next supplement worthy of consideration for PN is R-Alpha lipoic Acid (R-ALA). R-ALA has shown benefit in people with PN at a dose of 600 to 1200 mg /day. The following review gives some detail on ALA relative to PN :
' Several studies suggest alpha-lipoic acid helps lower blood sugar levels. Its ability to kill free radicals may help people with diabetic peripheral neuropathy, who have pain, burning, itching, tingling, and numbness in arms and legs from nerve damage. Researchers believe Alpha-lipoic acid helps improve insulin sensitivity. '
I think the last sentence from the above quote is especially of importance to PwP, because insulin resistance (IR) is considered a risk factor for PD and IR also causes more damage in PwP, including increased disease progression.
In the following review they discuss the significant negative effects that IR can have in PwP :
' Insulin resistance, one of the major hallmark for etiology of T2D, has a detrimental influence on PD, negatively affecting PD phenotype, accelerating its progression and worsening cognitive impairment. '
Melatonin
Another supplement worthy of consideration for PN is Melatonin because it is well noted for protecting the nerves, improving insulin resistance, increasing insulin sensitivity, reducing damaging oxidative stress and reducing multiple inflammatory mediators and cytokines. Here is a study that suggests that melatonin is helpful in nerve repair :
' The findings of the current study showed that melatonin was involved in repair of peripheral nerves thus further analyses were performed to explore the mechanism underlying the role of melatonin in repair of peripheral nerves. Analysis showed Parkin expression increased in PNI and TBHP-treated RSC96 cells (Fig. 1). Moreover, TBHP increased mitochondrial ROS production, mitochondrial damage, apoptosis, and inhibited autophagy flux in RSC96 cells (Fig. 2). '
Berberine
The sixth supplement I would like to add to the list is Berberine which is now thought to regenerate nerves as outlined here :
' Notably, experimental data implied that berberine may promote nerve regeneration through IGFR-mediated JNK-AKT signal pathway, which may be a potential therapeutic agent for nerve injuries therapy and need to be studied for clinical investigations. '
Supplements
1. Vitamin B1 As Benfotiamine
2. Vitamin B6 as P5P
3. Vitamin B12
4. R-Alpha Lipoic Acid
5. Melatonin
6. Berberine
Conclusion
So the above 6 supplements have shown benefit for fighting PN and while there are plenty of others, these are six very common ones that are readily available, inexpensive while having good safety profiles. The B1, B6 and B12 combo have been a mainstay against PN for many years, but doctors seem to generally not mention them to their patients. ALA /R-ALA is a more recent addition, but it has many anecdotal reports of benefit against PN. Melatonin would be the second newest of the bunch, but when you consider its multiple known methods of action against PN, the question would be, why did it take so long to get recognition in nerve repair? Berberine would be the newest addition, but like melatonin it is noted for nerve regeneration which is very important in terms of reversing PN. It is worth noting that all of the above have shown benefit in fighting PN, but it is also worth mentioning that all of the above have shown varying degrees of benefit in PD or PD models.
Art
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Thank you for sharing this very helpful information. Not only an excess of B6 can be very harmful, but also a severe deficiency, as in my case. Today, for the first time, my neurologist considered that there might be a connection between B6 <> my PD medication and the severe PN. "Try it for 3 weeks with a B6 supplement if you like."… Why is this aversion to nutritional supplements among doctors anyway. In any case, have all B values tested. To measure is to know!
One week of “self medication" with vitamin B6 (P5P) seems to have immediate effect. The rapidly progressing neuropathy may have been halted and is causing fewer symptoms. In addition I was able to halve my Sinemet medication without any problem and a further reduction seems even possible!!! The negative spiral is hopefully broken…
That is wonderful news, I am so glad! Back in 2019 I had the same kind of reaction when I added a little methylfolate to my B12 - just amazing. I worked out my B6 was about 8% of the way through my range, and yours was minus 41% through your range. I have doubled my dose, which is still small, and shall see if a slightly higher intake makes any difference. Best wishes to you x
Hi, how kind of you to ask. Not sure, I'm afraid. Not been too well, possibly another bout of covid, and it has got much colder so other syptoms are worse (due to low thyroid hormones which I can't yet get help with) and my B12/folate disorder makes the picture confusing. I am awaiting new test results for the latter and do seem to be making some small steps in the right direction, so I do think the B6 will be playing an important supporting role if my genetic problem(s) turn out to be what and where I think they are!
How are you doing, yourself? I hope you have maintained or even increased your improvement.
How unfortunate that your situation has not really improved after all. Indeed, there is still a lot unclear about the interaction of vitamins, minerals and medication. If you can already see the impact of a simple B6 deficiency, which is related to all B vitamins, you will need to know more about this and especially measure it.
My medication is now down to 30% and back to my starting point of almost 2 years ago!!! However, the neuropathy in my feet and lower leg seems irreparable and will probably continue to keep me awake at night and further restrict me in walking.
I hope for you more clarity in your situation so that you can make a plan of action! Let's keep each other informed. 🍀
I agree - there is so much still not well understood about metabolism and interaction of vitamins etc, B12 and folate especially it seems to me. I am glad that you are making progress and am sorry that your neuropathy seems to have not improved. Are you getting injections for your B12 deficiency or just taking tablets/sublinguals? I know that nerve damage can continue to improve for as long as 5 years given sufficient treatment, so there may still be gains to make. Best wishes to you, and yes, let's stay in touch.
Very important for people to know that the cheap inactive form of B6 can be toxic and cause peripheral neuropathy, but not so with P5P. Also, taking carbidopa levodopa greatly increases the need for B6, but it should be separated by a couple hours, or a meal, from C/L.
right on time for me. Having tingling in my legs that was driving me nuts. Take already b12 but not as methilcobalamine...and need to get back to ALA...
thank you, PB! I did purchase P5P only a few days ago. Unfortunately my B1 has been sourced fron vitacost after a long time searching and put on repeat so benfothiamine may have to wait. No room in house for all these supplements!!!😂
Methylcobalamin doesn't suit everyone, so take it slow if you start - if you are taking hydroxocobalamin or adenosylcobalamin already you may not benefit from a change (although you may benefit from taking more than you are currently using), but if taking cyanocobalamin you may well get a benefit from a change to any of the others. (I don't have PD, other neuro and a B12 problem - I take all three, methyl, adenosyl and hydroxo., in divided doses and forms, to c 5000mcg daily)
Thank you...I get so confused with all the supplements pwp take however B’s are the ones I understand. I will confidently add Melatonin to the list now, thanks x
With melatonin, it is clear that some people can't tolerate it as it makes them sleepy the next day or otherwise feel off. If you do tolerate melatonin it has a multitude of health benefits including for PD. I tolerate melatonin well so I take 132 mg/day. If you do not tolerate melatonin, another consideration would be CDP Choline or Citicoline which both have shown the ability to improve nerve function. Citicoline has also shown benefit in PwP.
I have been taking melatonin continuously for many years at higher dosing levels with my current level at 132 mg per night. Most studies only go for months and I have only seen one melatonin study that went for 2 or 3 years in ALS patients at very high dosing.
Melatonin should be taken at night with only a few exceptions for severe conditions such as cancer or Covid-19.
Not everyone tolerates melatonin so it is always prudent to start low and work up to your desired dose to make sure you tolerate it.
Thank you so much Art for this post. It would seem from this article that Vitamin B1 Benfotiamine is the form I should be taking rather than the sublingual Thiamin Mononitrate I have been using ( which so far has not worked for me). I so appreciate the information share.
The test for vitamin B6 level is Pyridoxal(5) Phosphate, the biologically active form of vitamin B6. The reference range is 5-50 ug/L or 5-50 mcg/L and test levels are usually 30 mcg/L or less.
' In adults, vitamin B6 deficiency can cause inflammation of the skin (dermatitis) and a red, greasy, scaly rash. The hands and feet may feel numb and prickling—like pins and needles. The tongue may become sore and red, and cracks may form in the corners of the mouth. People may become confused, irritable, and depressed. They may have seizures. '
A relevant quote from the article regarding vitamin B6 toxicity :
' Patients typically experience symptoms of peripheral neuropathy, dermatoses, photosensitivity, dizziness, and nausea with long-term intake of dosages above 250 mg/day. Additional morbidity would include ataxia and dysesthesias. '
The above shows the importance of having an optimal B6 level, not too high or too low.
a combination of Hardys daily essential nutrients (12 per day) with added vitamers and Restore gold (16 per day) plus melatonin covers all of these with the safe version of vitamins plus lots of other useful compounds.
it is expensive so I buy the 3 pack as it is a bit cheaper. It does have 7 things in it and TUDCA is very expensive on its own so I am pretty sure it is cheaper than buying each individually, plus it is supposed to be quality controlled. If it works then I think it is worth it to feel better . I just figure it is part of the food hubby needs to feel his best. We cut down on meat and dairy so that offsets it slightly.
12 Hardys is the clinical dose that they do their clinical trials on. There are lots of different things in it at therapeutic doses and some of them are bulky like NAC, ALC ALA in their proprietary mix which is 320mg per 4 capsules alone or 960mg per day, then Mg is 600mg per day, calcium 1320mg per day, vitamin c 600mg per day etc.
I tried replicating it with individual products but it wasn’t any cheaper and very time consuming ordering and counting out them all individually so this is easier and I don’t think it is dearer. They have their own special chelation complex too NutraTek to make it more bio available,
16 restore gold. Again there are 7 things, 5 of which need 500mg-1500mg in clinical amount per day so it can’t be made smaller. They are bulky compounds.
Thank you for that LAJ! Plus you have already mentioned the other beneficial long term effects that your husband has gotten from them in terms of PD improvement!
Thank you very much for this information! My husband is experiencing symptoms of peripheral neuropathy that we are trying to determine if it’s from recent cervical disc fusion or PD (or both?). The supplements are worth a try regardless. Thank you!!
If you are trying to determine if the symptoms are caused by the recent CD fusion or is really PN, you can try applying a soft ice pack to the area where the surgery was performed, for several times a day for 3 days. In between applications of the ice pack, apply this topical pain reliever :
If you get no benefit from working on the area of the surgery, try the same routine on the neck down to between the shoulder blades for another three days to see if that offers relief and confirmation of where the nerve inflammation is originating. This is a non invasive approach to try and find the source of nerve inflammation.
The original post was at the limit for characters so I could not discuss dosing. In the review discussing vitamin B1 in the form of Benfotiamine, they mentioned 150 mg to 300 mg two times per day.
Vitamin B-6 in the form of P5P, you should get tested by your doctor to see what your current level is and then get well into the reference range of 5 - 50 mcg/L.
Vitamin B12, again it would be best to get tested to see where your B12 level is and then the doctor can advise on the best way to correct it if it is low. If it is very low he may give you shots of B12 to bring it up.
For Alpha Lipoic Acid (ALA or R+ALA), studies have used 600 mg /day.
For melatonin a dose for PN has not yet been established , but in a study 10 mg /day was shown to be beneficial for people with PD at lowering inflammatory and oxidative stress mediators. The dose is usually taken at night shortly before bedtime.
Here are several relevant quotes from this systematic review :
' Nonetheless, in the majority of cases, these diabetes-induced biochemical and histological alterations were reversed when melatonin was administered. It is worth noting that the administration of melatonin ameliorates the neuropathy caused by diabetes. Melatonin exerts these neuroprotective effects via various anti-oxidant, anti-inflammatory, and other mechanisms. '
' The result of the present study indicated that DN significantly reduced CAT, SOD, and GPx levels as anti-oxidant markers compared to the control group. These anti-oxidant markers were restored to normal levels with melatonin administration (Baydas et al., 2003a; Babaei et al., 2010; Metwally et al., 2018). '
' The result of the present study indicated that DN significantly reduced the expression of Nrf2 and HO-1 proteins as anti-oxidant markers compared to the control group. Melatonin administration restored these anti-oxidant markers to normal levels (Negi et al., 2011). '
' 3.2.3 Histological changes Histological changes are markers for identifying tissue damages induced by DN. DN induced an increase in GFAP and S100B levels, IHC score, DNA damage, liver damage, neurodegeneration, degeneration of the sciatic nerve, number of apparently degenerated fibers, axonal degeneration, demyelination, abnormal myelinated fibers, as compared to the control group, while treatment with melatonin reversed back these histological changes to normal (Baydas et al., 2003a; Negi et al., 2010; Negi et al., 2011; Zangiabadi et al., 2011; Afifi, 2013; Metwally et al., 2018; Magar et al., 2020). '
' This study aimed to review the harmful effects of diabetes on neuron cells/tissue. Additionally, the effects of melatonin administration on these detrimental effects were examined. It is reported melatonin is safe even in extremely high doses, tests on both humans and animals have shown that short-term usage of melatonin is quite safe. There have only been reported relatively minor adverse effects, such as lightheadedness, headaches, nausea, and tiredness. Exogenous melatonin has not been shown in any study to have the potential to cause any major adverse effects (Andersen et al., 2016; Oliveira-Abreu et al., 2021). '
Hi Art, as "the" HU experience expert with higher doses of Melatonin, I came across this recommendation from you.
“For melatonin a dose for PN has not yet been established , but in a study 10 mg /day was shown to be beneficial for people with PD at lowering inflammatory and oxidative stress mediators. The dose is usually taken at night shortly before bedtime.”
Could you perhaps reproduce the link of this study? For just over a month I have been using a low dose of Melatonin (1 mg) for insomnia with great success. So I am one of the lucky ones. Still, I have some hesitation to increase this to 10 mg for my PN, as a fairly permanent headache has occurred simultaneously. Could be coincidence, but I'd also rather try not to interfere with the currently very effective reduced C/L medication. Do you know anything more about this possible side effect? 🍀
Yes, there are at least three human studies using melatonin at 10 mg/day, 50 mg/day and 50 mg/day, all to positive benefits in PwP. Here is the link to the full study that you requested for the use of 10 mg/day in people with PD :
Here is a relevant quote from this human study in people with PD :
' Melatonin supplementation significantly reduced the Unified Parkinson's Disease Rating Scale (UPDRS) part I score (β −2.33; 95% CI, −3.57, −1.09; P < 0.001), Pittsburgh Sleep Quality Index (PSQI) (β −1.82; 95% CI, −3.36, −0.27; P = 0.02), Beck Depression Inventory (BDI) (β −3.32; 95% CI, −5.23, −1.41; P = 0.001) and Beck Anxiety Inventory (BAI) (β −2.22; 95% CI, −3.84, −0.60; P = 0.008) compared with the placebo treatment. Compared with the placebo, melatonin supplementation resulted in a significant reduction in serum high sensitivity C-reactive protein (hs-CRP) (β −0.94 mg/L; 95% CI, −1.55, −0.32; P = 0.003) and a significant elevation in plasma total antioxidant capacity (TAC) (β 108.09 mmol/L; 95% CI, 78.21, 137.97; P < 0.001) and total glutathione (GSH) levels (β 77.08 μmol/L; 95% CI, 44.29, 109.86; P < 0.001). Additionally, consuming melatonin significantly decreased serum insulin levels (β −1.79 μIU/mL; 95% CI, −3.12, −0.46; P = 0.009), homeostasis model of assessment-insulin resistance (HOMA-IR) (β −0.47; 95% CI, −0.80, −0.13; P = 0.007), total- (β −13.16 mg/dL; 95% CI, −25.14, −1.17; P = 0.03) and LDL- (β −10.44 mg/dL; 95% CI, −20.55, −0.34; P = 0.04) compared with the placebo. '
Also worth mentioning is that forum member Jimcaster recently updated on the forum his experience using 80 mg/day of melatonin which seems to have a positive benefit for him.
Btw, headache is a known side effect of melatonin supplementation, but there are ways around melatonin side effects using natural methods of producing more melatonin in the body without the unwanted side effects. On the other hand, if your main concern is PN, the other four supplements should be quite beneficial in combination.
If you are interested in an alternative to melatonin for PN and possibly PD, Acetyl L Carnitine is worth considering.
Thanks for this detailed explanation and info! Very promising and also the tip for Acetyl L Carnitine. I am trying to figure out if I can solve the headache problem first. If you have any tips for that I would love to hear them. Perhaps it is the interaction with a disturbed vitamin B6 level? After all, B6 causes the epiphysis in your brain to produce the substance melatonin and in September my B6 level was virtually zero.
Doing a full study of neuropathy and supplements, I found this somewhat confusing. The same supplements in which a deficiency can cause neuropathy also cause neuropathy with an overdose. When I had a pinched nerve in my thumb that wouldn't heal, the neurologist has me stop taking a supplement with 35mg zinc and another with 400 IU for one month, and the pinched nerve is healing. His main concern wasn't these dosages, but how much I was also getting in food.
Yes, vitamin B6 is well noted for requiring a proper balance in terms of peripheral neuropathy (PN). Too little and it can contribute to PN, too much and it can cause PN, but balanced, and it can reduce PN.
B12 and Folate are known to be significantly lower in PwP and it is thought that Levodopa is a contributing factor or the main factor for the reduced levels. So the standard treatment for PD can indirectly contribute to PN. So supplementing B12 is very likely a good idea if you have PD and are taking levodopa and even more so if you also have PN. These factors are a good argument for being as informed and proactive as is practical when it comes to your health.
Note: B12 is a cyanide compound, You need some, but understandably not too much. Tree nuts have cyanide that your body with change to B12. Thus, if you eat raw tree nuts regularly, you probably don't want to supplement more than what is in a normal multivitamin. Normally your body gets rid of the cyanide in raw tree nuts that you don't need. unless you eat over 50 ounces of raw sweet almonds. Bitter almonds have too much cyanide when raw. Raw almonds also have zinc and B6.
my husband takes all these supplements except alpha lipoic acid due to the fact it causes major indigestion yet the neuropathy seems to persist so is there something else that could help?
Acetyl L carnitine has synergy with alpha lipoic acid for PN.
CoQ10 has shown benefit in diabetics with PN. A more bioavailable form of CoQ10 is Ubiquinol.
Curcumin + Bioperine is also useful for PN.
It is also worth mentioning that fungal infections such as candidiasis and aspergillosis can also cause PN. Covid-19 antagonizes our natural defenses against fungus.
okay so he is taking the above and has avoided covid 19 (knock on wood) except for alpha lipoic acid - I have no idea how people can take this without having indigestion-we have both tried it and had a big problem with it
I guess we can try it. So far I have been very disappointed and I don't know how anybody can take this. Neither of us is diabetic. My right foot has a lot of arthritis due to an injury.
It happens. The two of you are obviously very sensitive to ALA. I can take up to three 600mg capsules per day and the same with NAC. In any case, there are the others that I mentioned.
For your right foot, you can try soaking it in a saturated solution of very warm borax laundry booster once a day for a month. I take it orally in a very significantly lesser dose and it has kept my arthritis in remission for the past 15 years.
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