Carbidopa uses up vitamin B6. Vitamin B6 is essential for all manner of biochemical wizardry, so it is not something we want to be short of. Vitamin B6 and carbidopa bind together and inactivate each other, so they cannot be taken at the same time. One way around this problem is to give up carbidopa entirely, which was the reason for the Hinz protocol. Another solution is to simply take them a couple of hours apart or separate by a meal.
It is essential to avoid pyridoxine, the version of vitamin B6 that causes toxicity:
The vitamin B6 paradox: Supplementation with high concentrations of pyridoxine leads to decreased vitamin B6 function
"Vitamin B6 is a water-soluble vitamin that functions as a coenzyme in many reactions involved in amino acid, carbohydrates and lipid metabolism. Since 2014, > 50 cases of sensory neuronal pain due to vitamin B6 supplementation were reported. Up to now, the mechanism of this toxicity is enigmatic and the contribution of the various B6 vitamers to this toxicity is largely unknown.
In the present study, the neurotoxicity of the different forms of vitamin B6 is tested on SHSY5Y [a human derived neural cell line] and CaCo-2 cells. Cells were exposed to pyridoxine, pyridoxamine, pyridoxal, pyridoxal-5-phosphate or pyridoxamine-5-phosphate for 24 h, after which cell viability was measured ...
Pyridoxine induced cell death in a concentration-dependent way in SHSY5Y cells. The other vitamers did not affect cell viability. .... Moreover, both pyridoxal-5-phosphate dependent enzymes were inhibited by pyridoxine. In conclusion, the present study indicates that the neuropathy observed after taking a relatively high dose of vitamin B6 supplements is due to pyridoxine. The inactive form pyridoxine competitively inhibits the active pyridoxal-5-phosphate. Consequently, symptoms of vitamin B6 supplementation are similar to those of vitamin B6 deficiency."
So the moral of this story is if you are supplementing vitamin B6, do not take it as pyridoxine, which is frequently what you get in multivitamins. Take pyridoxal-5-phosphate (P5P) instead. It is readily available as a supplement.
From what I have gathered, if the subject ever came up, the average neurologist would tell his or her πatients taking Sinemet to avoid using vitamin B6 because it reduces the amount of L-Dopa reaching the brain. But IMO, this would seem to be very bad advice since it ignores B6 binding by Carbidopa, and, as Hinz et al point out, B6 is essential for hundreds of reactions in the body. One glaring example to illustrate this is the link to homocysteine. High levels of homocysteine (say around 10-11µmol/L or higher) greatly increases the risk of many diseases, including cardiovascular, stroke, and Alzheimers. But Carbidopa binds up the B6 throughout the body and B6 is one of the nutrients most often cited as vital to keep levels of homocysteine low.* So telling patients to avoid B6 completely is putting them at heightened risk of heart disease and dementia, among other nasty options. What patients don't know can really hurt them.
* More in detail, we are told: " The most important nutrients that help lower homocysteine levels are folate, the vitamins B12, B6 and B2, zinc and trimethylglycine (TMG)."
Since returning to the use of Sinemet, I have been careful to follow your suggestion of supplementing with adequate PLP, but separated by a few hours from the carbidopa.
This makes good sense to me. So before I go to bed at night, I've been taking B6 (PLP), B12, and a B-complex--the latter to avoid imbalance among all the B vites. This may not be feasible for those who depend on Sinemet to sleep at night, but maybe they can move their supplementation to the a.m., as you do.
Thank you, Gio. After a 4-month delay, I finally studied this article. Most interesting to me was that I see this paper is probably where Dr. C. got his hypothesis of thiainine's abilty to cross the blood-brain-barrier via passive diffusion when administered in megadoses.
Every time I read these studies I am impressed by the incredible complexity of Cellular Life and its intelligence in managing these substances, after all it has an experience of millions of years of evolution of which it preserves the memory and knowledge. As you can see from this study, thiamina plays a mainly energetic role with brain cells as well as having other non-energy roles with other organs. This means, as dr C says in an interview, that thiamina has a restorative function, i.e.that will help the part of suffering cells to carry out their activities. So it is not a cure. In my opinione the mitochondria responsible for energy production are damaged in PD patients according to a gradual scale for each of us different as the extent of the injury is different. So that part of suffering cells will be helped to regain its ability to produce levodopa and IMO will give that initial improvement that I myself have found and is even reported by some. Dr C says also that B1 has a neuroprotective effect over time, but this only time will tell us. In four years of use of b1 I'm quite satisfied.
Here I went off topic and I hope Park_Bear forgive me.
I don't take carbidopa, but I have had a little experience chasing B6 toxicity. I wonder if B6 toxicity may be related to a functional B12 deficiency; if they are two sides of the same coin, then increasing B12 may help avoid B6 toxicity. And of course, only take P5P, not pyrixodine. Has anyone here tried this?
I had neuropathy and paresthesia for many years.
For a time I thought it might be due to vitamin B6 toxicity, because my B6 serum levels tested high. I only had taken normal doses of P5P (pyridoxal-5-phosphate), not high doses of pyridoxine, but I wondered if perhaps I accumulated B6 for some reason. I eliminated B6 from my supplements, but it did not help. I joined a facebook group on B6 toxicity, where other people went to great trouble to eliminate B6 from their diets. Interestingly, many members reported developing toxicity from P5P, even though the literature says it's safe.
Eventually I discovered B12 injections, which largely eliminated my neuropathy and paresthesia. This makes me wonder if people with "B6 overdose" or "B6 toxicity" are perhaps really suffering from "B12 deficiency"-- and rather than avoiding B6 (which is very difficult), they might find relief by restoring the ratio between B6 and B12, by increasing their B12.
I did not have B12 deficiency shown in my blood tests (serum B12 and MMA were okay, probably because I took B12 sublinguals), but the B12 injections seem to have fixed whatever problem I had. I tried injections because of a note on this page: stichtingb12tekort.nl/weten... "As there is no ‘golden’ test, patients with clear neurological symptoms, and no other obvious cause for those problems, should be treated with B12 injections." So I tried them, and they worked.
Thanks for your informative post Genesurf. I remember reading a similar story years ago -- but the website it was posted on has disappeared. I think it's common sense to try to treat any sort of neuropathy with B12 -- it's worth a try at the very least. That B6 Toxicity Facebook group is just bizarre. I don't know WHY they even have it as they won't allow anyone to post anything that "isn't backed up by science". Which translates to "isn't backed up by drugs."
Anyway, it's also worth noting that B6 lowers folate levels, so supping with folinic or methylfolate may help with B6 toxicity. I can post a link to the study if you like.
Due to the problems of balancing my B6, my peripheral neuropathy is deteriorating more and more and now seems irreparable due to too much damage in the nerve pathways. Your experience Genesurf with a largely restored neuropathy by applying B12 injections intrigued me. Has your situation/medication stabilised or changed in the past 4 years with any new insights?
Thanks Art, it was already in my PD library! I am currently having my homocysteine value examined for the first time via a blood test. If it is normal, can you assume that there is no problem with B12 and other B vitamins?
Diagnostic Accuracy of Holotranscobalamin, Vitamin B12, Methylmalonic Acid, and Homocysteine in Detecting B12 Deficiency in a Large, Mixed Patient Population
"Overall, the area under the curve (AUC) for the detection of subclinical B12 deficiency was highest for HoloTC (0.92), followed by MMA (0.91), B12 (0.9) and Hcy (0.78).
Generally, MMA has been regarded by some authors as the most accurate marker [5], whereas HoloTC has been described as the earliest and most sensitive marker of B12 deficiency [22]. Nevertheless, since all four markers have nonspecific factors that influence their concentrations, it is generally acknowledged that there is no single best marker of B12 deficiency [13, 24]."
Per figure 2 it looks like there are cases where B12 deficiency may be missed by homocysteine test - sensitivity less than other measures.
I don't think you can assume your B12 level or other B levels are in range unless you actually have them tested. People with PD tend to be deficient or insufficient in B12. Levodopa is thought to lower B12 levels as well as folate level. I think the whole B vitamin group is important for everyone, but especially for people with PD.
To that list of peripheral neuropathy supplements, I would add Berberine which helps regenerate nerves and is also good for PD.
I just got my blood test results after 3 months without supplements. The B6 and B1 values had become much too high due to supplementation after an initial severe B6 deficit, so that my C/L medication no longer worked properly and the peripheral neuropathy further worsened.
My first homocysteine measurement appears to be within the norm but at the upper limit. B12 within the norm, but quite low, B1 just within the norm, but at the lower limit. B6 again serious deficit!
With a daily carbidopa/levodopa intake of 65/500 and healthy food (MIND diet), I think a supplementation of B vitamins for me (and maybe other PDers too) is absolutely necessary. I will halve the initial recommendation of park_bear to take the amount of Carbidopa as a guideline for B6 in P5P form to avoid new stacking and overdose. For the remaining B vitamins, a normal B- complex without B6 (or possibly with P5P) seems necessary. That will be difficult to find. Does anyone have recommendations? 🍀
Seeking Health brand has a product they call B minus which is B complex using P5P without folate and B12. Jarrow has a fully loaded B complex that uses P5P.
B12 can erroneously measure as normal or even high normal when there's actually deficiency. See: ncbi.nlm.nih.gov/pmc/articl...
I still take B12 injections every 3-5 weeks. In the beginning I self-injected B12 ("B12 DEPOT" Rotexmedica brand, 1mL adenosylcobalamin) every 1-2 days for months, then gradually stretched out the period between shots. Now it takes 3-5 weeks before mild symptoms start returning; I watch for leg heaviness, exhaustion, yawning during exercise, feeling flat and mildly depressed, forgetfulness, life just feeling "too hard", tingling in feet, seeing sparkles/moving lights under my eyelids when my eyes are closed in the dark. 30 minutes after the shot I'm feeling cheerful and normal again.
My neuropathy/parasthesias have largely healed (took about a year), and I don't have the exhaustion much anymore.
I take a ton of supplements every day, so some of those might help too. It's a very long list but I can share if you are interested. Occasionally I take TTFD (allithiamine) when I start feeling a bit out of it, and it helps perk me up again.
The B12 injections are the key ingredient though-- I was already taking lots of supplements, which helped a little, but the shots resulted in rapid and dramatic changes. I had an immediate sensory improvement 20 minutes after the first shot (suddenly and unexpectedly the colors looked brighter, sounds were crisper, tingling was there but different), which wore off after about 6 hours. The second shot's improvements lasted about 7 hours, etc. I had been taking sublingual B12 prior to the shots, so my blood tests looked fine, including homocysteine. I don't know why B12 injections work for me but they do.
Like the link I mentioned before (stichtingb12tekort.nl/engli... ) said: When anyone has mysterious neurological symptoms, try B12 **injections** regardless of blood test results. They're cheap, and you'll know quickly whether they help or not. You can get methylcobalamin B12 shots at some doctor's offices, day spas, medical (botox) beauty clinics, and weight loss places. They're often advertised as "energy shots" for about $35, no prescription needed. Try googling for "B12 shots" in your area... maybe search Groupon. If shots work for you, self-injections cost less than $1/shot. I get needles and syringes by prescription from my doctor, and order the Rotexmedica B12 ampules online from overseas.
One note-- after a few shots I started having rebound fatigue/fogginess, so I investigated and discovered that B12 shots deplete potassium. So now I drink potassium water after the shot and I don't have any rebound fatigue.
BTW the standard homocysteine range is too high, you should be at 8 or below.
Hi genesurf, thank you so much for your comprehensive update. Very informative, especially with regard to the possible unreliable residual values of B12. In the meantime I have started the oral supplementation of the various B vitamins again and wait and see what the following test data shows. Interestingly, a friend of mine who heard at the time that I had been diagnosed with PD immediately pointed out the importance of B12, because that had caused problems for her father. However, during that period I still had a blind faith in my neurologist and the proposed approach. I now look at that rather differently. After all, at least as important as the standard C/L medication turns out to be the possible imbalance of vitamins and minerals, your mental state, physical training and your diet, about which not even a word has been said at that time.
The concomitant neuropathy in particular is causing by this negligence the biggest problems at the moment, especially with declining muscle strength in my feet. So anything you want to share from experience about possible supplements in addition to the B12 that could possibly help slow down the PN in combination with the PD, I would definitely love to receive from you! You can also message me via chat if you prefer.
I will certainly take your warning of the possible interaction of B12 with potassium with a possible impact on neuropathy as well. In any case, I think it is important to test this next time during the blood test. Of course, it is hopeful that the B12 neuropathy could be reversible, as you have experienced for yourself.
When taking B vitamins I combine full doses of B12/methylcob 5,000 mcg, P5P 20 mg, methylfolate 400 mcg, thiamine 100 mg, biotin 5,000 mcg and riboflavin 100 mg, 100 mg niacin, 100 mg niacinamide, to mimic a high dose B complex vitamin. I don't think taking a single B vitamin, even thiamine as monotherapy, is a good solution considering B vitamins work best when taken in unison. As for B12 I have also tried taking hydroxocobalamin and adenosylcobalamin - anything but cyanobobalamin (which can be converted into hydroxocobalamin when exposed to light). So for those of you on high dose thiamine therapy take the other B vitamins with it. Perhaps combining the other B vitamins with high dose thiamine may make the therapy to work better.
The active forms of folate are actually more efficient in facilitating cell division since they do not need to be converted first. There is no free ride or easy out on this issue.
Those studies do exist, but usually in combination with B12, as mentioned by park_bear in his article. In such studies, there is often a relatively high intake, which however, is applied in the USA standard in supplements!
But if you take low-dose B vitamins, there is no problem. In Europe, such a B9 low dosage of 200 microgrammes B9 is now relatively easy to find.
Slowly, the realization is also starting to sink in that the excessively high dosages of B12, up to 40,000% (also in some 'safe' B complexes), are not as harmless as previously thought. Here too, the recommendation is for a dosage of 100% of the daily requirement, which is 2.5 micrograms! Keep in mind that this is an extra supplement, as most of us already get enough through our diet.
I have included the dosages of B6, B9, and now B12 in the list of lower-dose B complexes that I have reviewed together. Make good use of it.
I take methyltetrahydrofolic acid (Methylfolate) and methylcobalamin because these 2 B vitamins aid in the production of red blood cells. I have the 'trait' of Mediterranean anemia/thalassemia beta, inherited from 1 parent, and have irregularly-shaped (and smaller) red blood cells. Health wise Methylfolate aids in my energy and vitality. People with MTHRFR gene mutations take prodigious amounts of Methylfolate with no consequence:
Silvestrov, I have the MTHRFR mutation and my doc prescribed 5 mg a day of folic acid. Why do you recommend not taking folic acid? Is it because it’s not converting? I’m taking that with B12 and B6.
That mutation means your body cannot convert folic acid into its active form, methylfolate. Particularly in this situation consumption of large amounts of folic acid is exactly the wrong thing:
"The hazards of excessive folic acid intake in MTHFR gene mutation carriers: ...
this assumed “holy grail” supplement is actually being shown to have more risks than benefits. This is in particularly large doses, around 4-5mg, and in certain patients with the Methylene Tetrahydrofolate Reductase (MTHFR) Single Nucleotide Polymorphisms (SNPs)... when the MTHFR SNP is present, this external supply of synthetic folic acid that is unable to be fully processed, accumulates and can actually become hazardous....
An increase in unmetabolized folic acid can lead to ... an immune dysfunction by dysregulation of natural killer cells [3,4]. This excess folate decreases their innate cytotoxic effects leading to increased tumorgenesis. Increased folic acid has been linked to accelerations of leukemias, colorectal and prostate carcinomas [5,6]. In a recent large clinic trial in the US and Canada, a 1mg supplement of folate was given to patients with a history of colorectal cancer. At the 3-5 year follow up mark, there was found to be 67% of increased risk of invasive colorectal adenomas or advancement of previous lesions, as well as a more than 2x increased risk of at least 3 colorectal adenomas and prostate cancer [3]."
I wrote about about the increased cancer risk due to folic acid consumption here:
I presume your folate levels have been checked and they are low. (If it has not been checked, do so first before supplementing.) If so, I would take a small amount - 400 µg (=.4 milligram) of methyl folate, the recheck your levels at your next regular bloodwork..
Thanks PB! Just checked I’m 31.8 and max is 30.4 according to UCLA tests. Greatly appreciated! I was at 26.2 a year ago. I increased B12 and now take 10mg of B6(p5) and reduced my homocysteine to 10. (I’ve been taking 3 mg of folate daily. Will reduce to 1 and look into methyl folate ASAP . Again, thanks so much.
My mom takes her sinemet every 2 hrs until bed when she takes her sinemet Er.
I can’t figure out how to add in B6 because there is no window. Any ideas?
This makes me lean even more to getting her the Duopa pump so no Carbidopa will be needed and I can focus on balancing her vitamins to normal.
She is only 71 and already showing signs of dementia. She is unable to do anything on her own. We have pretty much around the clock care for her to keep her safe from falling etc.
If you can get her switched over to the ER version during the day that would involve larger doses less frequently and give you more window for the B6. With as much Sinemet as she is taking her B6 is likely to be heavily depleted.
You can try giving the B-6 at the one hour midpoint between Sinemet doses and see if it interferes with the Sinemet effectiveness. If that does not work you could try giving the B-6 during the course of a meal at the midpoint in time between the Sinemet doses.
This has 20 mg of P5P which is probably not enough if she is taking large amounts of Sinemet. Folate supplementation should be avoided unless a person specifically has low blood folate levels. See my writing here for why - Folate Supplementation Carcinogenic tinyurl.com/ycdrz5lj
See also my recent comment about folate higher up on this page.
For B-12 I use Seeking Health Adeno B-12, which is supposed to be helpful for the generic version of Parkinson's:
Ok, now here is another issue to complicate things.......I read recently on here about not taking P5P If you are taking SSRI because of serotonin syndrome.
I was taking my B6 with a general vitamin B supplement with my Rytary at breakfast. It contained 60 mg of B-6. Apparantly 10-25 mg of B-6 is enough to block the Rytary...so I was not getting any dopamine from it. (I also take other dopamine agonists...pramipexole and cabergoline). Boy did I feel different today when I left out the vitamin!
It was like a bomb since I was taking 195 mg of Rytary.
"The inactive form pyridoxine competitively inhibits the active pyridoxal-5-phosphate"Park Bear, does this mean the 10mg of pyridoxine hydrochloride in Emergen-C that my PWP takes every morning completely wipes out all the P5P he may take in a separate supplement?
Thank you! I like the doctor who makes seeking health. I’m part way through his book. I know folic acid is bad but folate is new to me. For B12, I use methyl B12 from JarrowI hope that one is okay.
PB: I experimented with taking p-5-p when I woke in the middle of the night, since that was the best time for me to separate it from my Rytary. My Rytary has not worked all day today. Any thoughts?
" in vitamin B6. values (as pyridoxine.HCl) among laboratories: 1.64—4.55 μg/g for whole wheat flour, 3.02-5.5 for non-fat dry milk, 5.38-20. 6 for Brewers yeast"
That means to get at most a single milligram of pyridoxine a person would have to consume at least a couple of ounces of brewer's yeast. To satisfy the high vitamin B6 requirements of Parkinson's patients taking levodopa medication brewers yeast is not a practical source.
Thank you so much. I take 25/100 Sinemet 5 x a day and a regular multi super b complex that has pyridoxine as the B6. After reading your information, it looks like I need to stop the multi vitamin and look for P5P in liquid form. I see B 12 under Sigform but not B6. Is there another brand you recommend?
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URIDINE: Why LD/CD Users Should Consider It
park_bear made a very compelling argument for taking P5P (active B6)
Vitamin B complex ?
Review of Dr Marty Hinz amino acid protocol for the treatment of Parkinson’s Disease
