A restriction or prohibition that has survived almost 50 years (1975-2020) without any scientific reason since levodopa was linked to carbidopa or benserazide.
by
Jesus Marquez Rivera
Project "Parkinsons Here and Now"
(2012-2021)
"What is Science? Learn from Science that you must doubt
of the experts... Science is the belief in the ignorance
of experts. Each generation that discovers something
from its experience must pass that on, but it must pass
that on with a delicate balance of respect and disrespect…"
Richard Feynman, Nobel Prize in Physics 1965.
Does it make sense to currently restrict vitamin B6 so severely since taking Sinemet (Levodopa with Carbidopa), Madopar (Levodopa with Benserazide), etc?
Our answer is categorical: no sense at all (within the scientific and reasonable limits set by government recommendations, information in the package leaflets of levodopa manufacturers and publications of prestigious neurologists: 1.3 to 25 mg/day in adults, unless specifically indicated by the doctor: age, diseases, medications, etc.).
Today, this is a prejudice, inherited from the years when levodopa was administered alone and which has survived for too long against the opinion and the writings of numerous neurologists and against what the manufacturers of Parkinson's drugs report.
LEGAL AND ETHICAL WARNING. Although what is stated in this article seems to me to be very cautious and to have very solid bases (such as the writings of famous neurologists or the leaflets of the three main manufacturers of the drug levodopa in its different varieties: Sinemet, Madopar and Stalevo), each specific case should be consulted with the doctor or the pharmacist. The lack of this vitamin is terrible. But excess can be too. We must move forward decisively, but also with caution.
Don't forget to consult your neurologist about any changes.
INDEX
1. Previous presentation.
2. Introduction.
3. Information sources: drug's package leaflets, neurologists' manuals, etc.
4. Conclusions and final advice.
5. Epilogue. Another key piece of the Parkinson's puzzle?
6. Appendix. Some "curiosities" about vitamin B6.
1. PREVIOUS PRESENTATION. Importance of vitamin B6 and its relationship with levodopa and carbidopa/benserazide.
VITAMIN B6 (pyridoxine, pyridoxal phosphate - which has been called the most versatile coenzyme in Nature because it participates in more than 140 biological reactions, 4% of the known ones (Percudani 2003), etc.) is essential to convert levodopa into dopamine, inside and outside the brain. But in the rest of the body, dopamine causes major problems and can no longer cross the barrier that protects the brain. So it doesn't work. That's why levodopa is given and must be protected until it is "safe" in the brain.
Carbidopa/benserazide (which also cannot pass through the barrier that protects the brain in any significant amount) is added to levodopa to reduce this conversion outside the brain, preventing the action of the enzyme that performs this transformation - which is dependent on vitamin B6, hence the limitation of potent vitamin supplements - and this is achieved:
- reduce nausea and vomiting.
- reduce damage to the stomach, heart, etc.
- allow 25 % of the ingested levodopa to reach the Central Nervous System and not 1-5 %, as was the case with levodopa alone (that's why the doses of levodopa alone used by Cotzias and the famous Oliver Sacks from "Awakenings" in the late 60's, had to be so high, with unbearable adverse effects). The use of L-dopa since 1967 and of decarboxylase enzyme inhibitors in the early 1970s and officially since 1975, allowed the use of much lower doses, with less negative effects therefore.
Since 1975 it has been insisted, without any foundation, that the patient treated with Sinemet, Madopar and Stalevo (the latter since 2003), must be very careful with foods rich in vitamin B6 (my father was even forbidden to eat pistachios, one of the foods richest in B6 - about 50 pistachios contain 0.5 mg) and supplements (even multivitamins that have 1.5 or 2 mg).
Here we defend that such a severe restriction makes no sense in general (unless the doctor considers it necessary due to the special sensitivity of the patient or his or her specific circumstances, which can only be assessed by the doctor) and, furthermore, is harmful to the Parkinson's patient: because WITHOUT SUFFICIENT VITAMIN B6, IT IS NOT POSSIBLE TO PRODUCE SUFFICIENT DOPAMINE. Levodopa would cross the blood-brain barrier perfectly, but since there is no necessary vitamin B6 (restriction in diet and supplements, expenditure of the existing one in reducing the high homocysteine in patients and more in those who take levodopa, deficit in most of the population and more in Parkinson's patients, etc.), it could not be converted into dopamine.
Despite the fact that it is often said that there are no problems with vitamin deficiencies in developed countries, that this myth called a "balanced" diet is sufficient, some studies claim otherwise. One found that 100% of 174 university students tested had some degree of vitamin B6 deficiency (Shizukuishi 1981). Another larger study of 11,658 adults found that 71% of men and 90% of women did not meet the recommended daily intake (RDI) of vitamin B6 (Kant 1990).
The release of the taboo on vitamin B6 in doses of up to 25 mg per day (from mild foods and supplements such as brewer's yeast and vitamin and mineral complexes or slightly more potent from all the B-complex vitamins) will be a step forward in improving the lives of Parkinson's patients: by facilitating dopamine synthesis and reducing the level of homocysteine. Two concrete actions we can already do.
After reading this paper, if you feel it is appropriate, we invite you to correct any website or document by removing that old and unfounded information since levodopa was introduced with carbidopa or benserazide (1975). Or communicate it (with the respect Feynman asks in the opening quote) to anyone who has that misinformation.
2. INTRODUCTION.
If I had read the title of this booklet 26 years ago, when my father was diagnosed with Parkinson's in 1994, I would have been shocked. I would have thought the author was a provocateur. But I assure you that nothing could be further from the truth. I invite you to read it to the end and judge for yourself whether there are reasons to support such a claim or whether it is unfounded.
In recent years a revolution has begun in the world of Parkinson's disease that cannot be stopped. You may not have noticed it yet, but if you look at a large enough body of scientific studies, publications, etc., for as long as it takes, you can see that studies are accumulating on the value of nutrients in the prevention, relief and treatment of Parkinson's, both epigenetic and deficiency studies, epidemiological studies, etc. Words such as genes, homocysteine, dyskinesias, prevention, dementia, improved mobility, etc, are increasingly linked to others such as folic acid (vitamin B9), vitamin D and GDNF, thiamin and riboflavin, magnesium, silymarin from milk thistle, NAC or glutathione, coenzyme Q10, ascorbic and dehydroascorbic acid (the active and oxidized forms of vitamin C - the latter can enter the brain and mitochondria to be returned to its antioxidant form once inside, thanks to glutathione, which is a fascinating mechanism)...
Vitamin B6 is as important as levodopa or even more.
There are 6 forms: but the most important are pyridoxine and pyridoxal phosphate, active form and coenzyme:
1. ESSENTIAL to convert levodopa into dopamine, as well as tryptophan (actually 5-HTP) into serotonin (itself the precursor of melatonin) and niacin (1 mg needs 60 mg of tryptophan and many vitamins and minerals), glutamate into GABA, etc. (Gerster 1996, Combs 2012). DOPAMINE, SEROTONIN AND GABA. I don't think more should be added.
2. Reduce homocysteine by a different route (Wilcken 1998) than that used by vitamins B9 and B12 (Reutens 2002, Postuma 2006).
3. Prevent and alleviate dyskinesias, both those caused by levodopa and neuroleptics, as it has a role in almost all possible responsible mechanisms (Lerner 2007, 2015; Umar 2016). There are numerous previous studies on this subject (Sandyk 1990, Lerner 2001, Lemno 2002).
4. Perform the more than 300 functions as pyridoxine and pyridoxal phosphate - active form and coenzyme of vitamin B6- (Gropper 2013).
A Dutch study published in "Neurology" states that a low level of vitamin B6 (less than 0.25 mg per day, when the recommended daily amount would be around 1.5 or 2 mg per day) increases the risk of Parkinson's by 54% compared to the higher level (De Lau 2006).
In a hospital-based study, 249 patients with Parkinson's disease and 368 healthy patients reported on their dietary history. After adjusting for other factors, low intake of vitamin B6 was associated with an approximately 50% increased risk of developing Parkinson's disease (Murakami 2010).
The limitation on vitamin B6 intake should be adequate, not more.
Just as levodopa must be taken at the proper dose, so must vitamin B6. Too much causes damage, but not enough also causes damage. The same is true for every natural or man-made substance: salt, sugar, paracetamol, aspirin...
3. INFORMATION SOURCES.
1. The package leaflets of the medicines Sinemet, Madopar and Stalevo (between 10 and 25 mg).
2. Book by neurologist Ahlskog (25 mg.)
3. Books by neurologist González Maldonado (food and multivitamins without restriction, low doses of 100 mg for dyskinesia by neuroleptics citing studies such as that of Sandyk in 1990).
4. Kathrynne Holden. The most famous nutritionist specializing in the disease. Collaborator of the National Parkinson Foundation. (No problems with food and supplements up to 15 mg).
5. The U.S. government's Institute of Medicine. (No more than 100-200 mg).
After scrutinizing books on Parkinson's and Levodopa, and looking with PubMed at scientific studies published over the past 60 years, it seems clear to us that since 1975 (the year the FDA approved the use of Carbidopa along with Levodopa - Sinemet - to treat Parkinson's) there is no basis for banning foods rich in vitamin B6 or mild supplements that include vitamin B6.) For higher doses in order to treat dyskinesias, it is essential to consult a specialist and receive his supervision for possible adverse effects (studies have been carried out with up to 1200 mg/day, but as there is a risk of damage to the nervous system, they should only be carried out by a specialist).
1. The package leaflets of the medicines Sinemet, Madopar and Stalevo (between 10 and 25 mg).
Merck, the manufacturer of Sinemet, informs us in the package insert:
"Pyridoxine hydrochloride (vitamin B6), in oral doses of 10 mg to 25 mg, may reverse the effects of levodopa by increasing the rate of aromatic amino acid decarboxylation.
Carbidopa inhibits this action of pyridoxine; therefore, SINEMET can be given to patients receiving supplemental pyridoxine (vitamin B 6)."
Source:
merck.com/…/pi_circula…/s/s...
Roche, the manufacturer of Madopar, and Novartis, the manufacturer of Stalevo, are expressed in similar terms.
2. Book by neurologist J Eric Ahlskog (25 mg.)
Renowned neurologist J Eric Ahlskog, on page 426 of his book "The New Parkinson's Disease Treatment Book: Partnering with Your Doctor To Get the Most from Your Medications", 2nd Edition, says he recommends that all his patients take levodopa-carbidopa (Sinemet) - the same would be true for levodopa-benserazide (Madopar) - vitamins B6, B9 and B12 as a preventive measure against elevated homocysteine:
Folic acid (folate)-2.5 mg;
Vitamin B12-1-2 mg (1000-2000 mcg);
Vitamin B6-25 mg
He claims that while most neurologists do not recommend these vitamins, he does so on the basis that it is a no-risk thing, and in the face of possible benefits, the objections are meaningless. He recommends ignoring the limitations on vitamin B6, within reasonable limits.
And he claims that the restriction on vitamin B6 has persisted since the days of levodopa alone, but since the addition of carbidopa to levodopa it doesn't make sense, although it does still surface in books and articles from time to time.
3. Books by neurologist Rafael González Maldonado (food, multivitamins, mentions doses of 100 mg/day for dyskinesia by neuroleptics citing studies such as that of Sandyk in 1990).
"The strange case of Dr. Parkinson" (March 1997), p. 129:
(This book has already been translated from Spanish to English. Essential.)
"VITAMIN B6 VERSUS LEVODOPA
Vitamin B6 competes with levodopa and decreases its action (only that, if taken together, no special damage occurs, it's just like taking less levodopa). This can only be seen with high doses of vitamin B6 so there is no need to suppress low-dose polyvitamin preparations.”
"Heterodox treatments in Parkinson's disease" (April 2004), p. 41:
(I don't understand how this book has not yet been translated into English. I still think it is the most important book ever written about Parkinson's disease for patients, caregivers and physicians.)
"7. VITAMIN B6 (PYRIDOXINE)
As vitamin B6 competes with levodopa 912,639 and slows its passage to the brain, it is insisted that it is not given to parkinsonians treated with this substance. This contraindication makes little sense with normal doses of vitamin B6 because now levodopa is taken in association with carbidopa (Sinemet) or benserazide (Madopar), which avoids these problems. 711 Formerly 61 was proposed to treat parkinsonism with vitamin B6. At low doses (100 mg/day) it improves yatrogenic parkinsonism, 1030 psychotic behaviour and levodopa dyskinesias. 1030".
4. Kathrynne Holden. The most famous nutritionist specializing in the disease. Collaborator of the "National Parkinson Foundation".
Kathrynne Holden. “Parkinson’s Disease: Nutrition Matters”, pág. 8-9. National Parkinson Foundation.
"Vitamin B6 and Parkinsons disease.
Before the combinations of levodopa/carbidopa and levodopa/benserazide were produced, people with PD were prescribed levodopa alone. It was found that vitamin B6 prevented the absorption of the levodopa, so people were advised not to eat foods rich in B6, or to take B6 supplements.
Now, however, the medication commonly used combines carbidopa or benserazide with the levodopa. These “protect” the levodopa, so that vitamin B6 in reasonable amounts is no longer thought to be a problem. It’s generally recommended that vitamin supplements for people using carbidopa-lev-odopa or benserazide-levodopa contain no more than about ten-fifteen milligrams of B6 daily; some people can tolerate more than that, others may be more sensitive. If you are sensitive to B6, or if you need to take very large amounts (over 15 mg), take the B6 at least two hours apart from the levodopa.You should inform your physician if you intend to use such large supplements of B6. Food sources of B6 include chicken, fish, pork, eggs, brown rice, soybeans, oats, whole wheat, peanuts, and walnuts, also fortified products such as cereals."
5. The Food and Nutrition Board of the U.S. Institute of Medicine.
U.S. authorities set the unobserved adverse effect level at 200 mg per day and the safe upper limit at 100 mg per day in adults to prevent the risk of sensory neuropathy in virtually all individuals.
Below 200 mg no harm has been reported (Bender 1999).
Cases of sensory neuropathy have occurred at or above 1000 mg per day. Some cases at 500 mg and below. Several studies have been carried out with very high doses of up to 1200 mg/day to treat dyskinesias without negative effects, but under strict medical control (Lerner 2007).
4. CONCLUSIONS AND FINAL ADVICE.
The same manufacturers of Sinemet, Madopar and Stalevo say with total clarity that now, Carbidopa can be taken with a pyridoxine or vitamin B6 supplement (at least up to 25 mg). Why this concern of these prestigious pharmaceutical multinationals? Because without enough vitamin B6, levodopa cannot be converted into dopamine in the brain. The drug would be ineffective.
It seems no coincidence that this is the amount of vitamin B6 that the prestigious neurologist J Eric Ahlskog prescribes for his Parkinson's patients: 25 mg of B6 along with 2.5 of B9 and 1-2 mg of B12 (or 1000-2000 micrograms), to reduce the level of dangerous homocysteine (elevated in Parkinson's patients and more when taking levodopa).
FINAL ADVICE: BE CAREFUL.
In any case, you should always consult your neurologist. And if you feel bad, try lower doses and complete with food could be an option to propose to the specialist.
He may recommend that we avoid supplementation near bedtime so as not to disturb sleep. Although the study was done with 250 mg, a rather high dose that is not usual (Ebben 2002).
5. EPILOGUE: Another key piece of the Parkinson's puzzle?
"Only those who research in the past have a future, because
by researching the past, the future can be rediscovered.”
Julius Robert Oppenheimer, atomic physicist
We "investigate" the past (both remote and immediate) in the sense of searching, collecting and disseminating what we have found. Like a detective or like a miner who sifts the sands of a river in his sieve in search of gold nuggets.
It is up to researchers and medical specialists to find the form of administration, the dose, the combinations (perhaps with B9 and B12), in which vitamin B6 may be most useful in improving the lives of Parkinson's patients.
We insist that its importance is absolute, as much as levodopa or even more so:
1. ESSENTIAL to convert levodopa into dopamine, as well as tryptophan (actually 5-HTP) into serotonin (itself the precursor of melatonin) and niacin (1 mg needs 60 mg of tryptophan and many vitamins and minerals), glutamate into GABA, etc. (Gerster 1996, Combs 2012). DOPAMINE, SEROTONIN AND GABA. I don't think more should be added.
2. Reduce homocysteine by a different route than vitamins B9 and B12 (Wilcken 1998).
3. Prevent and alleviate dyskinesias, both those caused by levodopa and neuroleptics, as it has a role in almost all possible responsible mechanisms (Lerner 2007, 2015; Umar 2016). There are numerous previous studies on this subject (Sandyk 1990, Lerner 2001, Lemno 2002).
4. Perform the more than 300 functions as pyridoxine and pyridoxal phosphate - active form and coenzyme of vitamin B6- (Gropper 2013).
If I were living at the beginning of the 20th century and I were a doctor or biochemist, you would be tempted to investigate whether "Parkinson's diseases" (as some neurologists call it because of its extreme variety) could be, to a large extent, a disease due to a lack of vitamin B6 (deficient, subclinical) or, rather, a syndrome caused by a lack of various vitamins and other nutrients, which trigger a cascade of negative rectifications throughout the body, locating itself above all in the weak points of the Parkinson's patient: the substantiantia nigra and other areas of the brain, the liver, the blood-brain barrier, the intestinal flora, etc.
Once we have seen the functions that vitamin B6 fulfils, we cannot even imagine the health disaster that can be caused by a continued deficit of this vitamin over years or decades.
Already in 1941 studies were carried out proposing vitamin B6 as a therapy for Parkinson's (Baker, AB. Treatment of agitating paralysis with vitamin B6).
We have seen that one of the forms of vitamin B6 (pyridoxal phosphate) is INDISPENSABLE for dopamine to be formed from dopa and L-dopa - which is taken as the main medicine for Parkinson's - to be converted to dopamine within the brain.
INDISPENSABLE for the conversion of tryptophan to serotonin (the neurotransmitter of happiness, reduced in depressed Parkinson's patients, and precursor to melatonin, which regulates sleep); for the conversion of tryptophan to niacin or vitamin B3 (the lack of which produces pellagra with some neurological symptoms that closely resemble those of early Parkinson's); from glutamate to GABA (gamma-aminobutyric acid, which would be as much a part of Parkinson's as dopamine, according to Dr. Bernardo Sabatini, professor of Neurobiology at Harvard Medical School); and so on.
DOPAMINE, SEROTONIN AND GABA...
6. APPENDIX. Some "curiosities" about vitamin B6.
What is vitamin B6?
It is a water-soluble vitamin that belongs to the group of vitamin B. The recommended dietary allowance (RDA) for vitamin B6 varies from 1.3 to 1.7 mg/day in the United States (Food and Nutrition Board, Institute of Medicine, 1998) and is 1.4 in Europe (Commission Directive, 2008).
Vitamin B6 has three forms and three phosphorylated derivatives that act as coenzymes:
Pyridoxine - The most common form in fortified foods and supplements and pyridoxine phosphate (P5P).
Pyridoxal and pyridoxal phosphate (PLP) - coenzyme required for the synthesis of neurotransmitters.
Pyridoxamine and Pyridoxamine Phosphate (PMP) - coenzyme.
Pyridoxine, pyridoxal, and pyridoxamine are transported in plasma and red blood cells to the liver, where they are metabolized to mostly pyridoxal phosphate. Up to 90 % of vitamin B6 in the blood is in this form.
Vitamin B6 in food.
The plant foods richest in B6 (usually in pyridoxine) are brewer's yeast, nuts, wholemeal, etc. The richest sources of animal origin (in pyridoxamine) are the liver of calves and fish (salmon). Both forms are converted into pyridoxal phosphate.
The average assimilation of vitamin B6 from food is between 61 and 92 %. The level of pyridoxal phosphate in the blood corresponds to vitamin B6 consumed from food or supplements.
Between 40 and 70 % can be lost through excessive cooking. Vegetables protect vitamin B6 better from heat than foods of animal origin (Combs 2012)
All six forms are present in foods, so it is advisable to combine foods and supplements (usually pyridoxine hydrochloride).
It is very important for proper absorption of vitamin B12 and magnesium (helps magnesium to enter cells). And to convert tryptophan into niacin.
PDF link:
drive.google.com/file/d/1QA...
END
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