Niacinamide Parkinson's Connection?

[ilikecats]

I came a cross a thread on longecity called "niacin neurotoxicty" and its got me a little worried. this is the study: http://qjmed.oxfordjournals.org/content/98/3/215.full and this is the thread: http://www.longecity.org/forum/topic/20190-niacin-neurotoxicity/ . Niacinamide is really doing wonders for my arthritis and anxiety but i stopped taking it after reading that. I'm pretty young but Developing parkinsons is probably one of my biggest fears so this is kind of freaking me out. There are some very intelligent people on this forum and I was wondering if you could please give me some insight into this. Thanks

 

[ilikecats]

I know that niacinamide has been shown to have a neuroprotective effect in mice with MPTP induced parkinsonism but im still really worried about it.

 

[NathanK]

I had to stop my high dose niacinamide (with biotin) trial over 6 months ago. I was taking over a gram for a couple weeks before my head started to feel "floaty". I started getting arthritis in some fingers for the first time too.

I've noticed if I take too much then that will appear again quickly. It was these signs that told me that I needed to pull back my enthusiasm closer to Rays recommended dosage below 300mg/day. In your thread they somewhat gathered that any related negative consequence likely had a genetic predisposition component and my family has a history of Parkinsons.

I do question a bit of their seemingly interchangable use of niacin and niacinamide.

 

[Such_Saturation]

So some guy comes up with

I think there is something in this. At the beginning of this illness I took large doses of Nicotinamide because I read about it reversing Alzheimer's in mice. I developed a severe tremor that was only resolved on taking PRL-8-53. It was resolved very quickly and easily but it had been a very severe tremor.

Which could easily be hypoglycemia, and then stacks other obscure substances on top in a panic, as people from that forum always do. This only happens to one person and he even says later

I have taken NR since then. No tremor and I find it quite helpful

But it still starts getting quoted as evidence...

 

[ilikecats]

yeah youre right. But that isnt the thing thats got me worried. if you look at the conclusion of that study it says quite a few things that worry me. "Altering nicotinamide in the diet as a potential protective manoeuvre may work, but the dose may need to be individualized, and N-methyl compounds would still be produced, including N-methylated nicotinamide. Western societies who suffer more from PD may now have too much nicotinamide in their diet overall, and this may need to be addressed at the population level". They also say: "Parkinson's disease is also rare in regions such as Africa where pellagra still occurs, even though Black Americans get PD at the same rate as White Americans within a few generations The epidemiological data on nicotinamide dietary dose is therefore conflicting, and could fit with a ratio of pyridine intake that is skewed toward protoxic rather than protectant compounds. At an individual level, any safe intake may well differ between high and low methylators, and there may be a window with toxicity at the extremes". and theyre just talking about dietary niacinamide. I was using 3 grams of niacinamide. What do you think?

 

[High_Prob]

yeah youre right. But that isnt the thing thats got me worried. if you look at the conclusion of that study it says quite a few things that worry me. "Altering nicotinamide in the diet as a potential protective manoeuvre may work, but the dose may need to be individualized, and N-methyl compounds would still be produced, including N-methylated nicotinamide. Western societies who suffer more from PD may now have too much nicotinamide in their diet overall, and this may need to be addressed at the population level". They also say: "Parkinson's disease is also rare in regions such as Africa where pellagra still occurs, even though Black Americans get PD at the same rate as White Americans within a few generations The epidemiological data on nicotinamide dietary dose is therefore conflicting, and could fit with a ratio of pyridine intake that is skewed toward protoxic rather than protectant compounds. At an individual level, any safe intake may well differ between high and low methylators, and there may be a window with toxicity at the extremes". and theyre just talking about dietary niacinamide. I was using 3 grams of niacinamide. What do you think?

Hi Haidut (long time fan here) - What is your take on the conclusion of the study as mentioned above? I love the way you talk about Niacinamide and I get so excited about taking it. However, every time I am at the store and about to purchase, I think of this study and the fact that I have a family history of Parkinson's...

On second thought: Attention Haidut and/or anyone on the forum that has feedback concerning the study...

 

[paymanz]

any substance in excess can produce imbalance, especially in long term.and also when you take a big dose a bigger impurities you also ingest.go with ray peat's dose and be a little bit patient so it works.but im not an expert , just my

 

[High_Prob]

any substance in excess can produce imbalance, especially in long term.and also when you take a big dose a bigger impurities you also ingest.go with ray peat's dose and be a little bit patient so it works.but im not an expert , just my

Thanks Paymanz.

Maybe other Peat approved substances like Aspirin and Vitamin E would protect against damage from MPP + ( and possibly decrease the possibility of nicotinamide N-methyltransferase from converting 4-phenylpyridine into MPP+) so that we could be on the safer side when popping Niacinamide...

 

[High_Prob]

Selective destruction of dopaminergic neurons by low concentrations of 6-OHDA and MPP+: protection by acetylsalicylic acid aspirin. - PubMed - NCBI
Selective destruction of dopaminergic neurons by low concentrations of 6-OHDA and MPP+: protection by acetylsalicylic acid aspirin.
Abstract
We optimized a mesencephalic cell culture system to employ low concentrations of 6-hydroxydopamine (6-OHDA) and 1-methyl-4 phenylpyridinium (MPP+), neurotoxins known to trigger oxidative stress in dopaminergic cells. Both 6-OHDA and MPP(+) at 5 micro M reproducibly reduced the survival of dopaminergic neurons by 50-70% (p<0.02) without affecting the survival of the non-dopaminergic neuronal population. We found that 1mM of the non-steroidal anti-inflammatory drug (NSAID), acetylsalicylic acid (ASA), significantly (p<0.05) increased the survival of dopaminergic neurons exposed to either neurotoxin. The mechanisms underlying neuroprotection by ASA may be of therapeutic import in Parkinson's disease.



Acetylsalicylic acid and acetaminophen protect against MPP+-induced mitochondrial damage and superoxide anion generation. - PubMed - NCBI
Acetylsalicylic acid and acetaminophen protect against MPP+-induced mitochondrial damage and superoxide anion generation.
Abstract
The effects of 1-methyl-4-phenylpyridinium (MPP+) has been extensively researched due to its selective toxicity to dopaminergic neurons. Mitochondrial dysfunction which is common in the etiology of Parkinson's disease (PD), has been widely implicated in MPP+-induced toxicity. MPP+-induced mitochondrial dysfunction is believed to result in the generation of free radicals. This study was therefore performed to assess the effect of MPP+ on mitochondrial function and the ability of MPP+ to generate superoxide free radicals. Furthermore, we assessed the ability of the non-narcotic analgesics, acetaminophen and acetylsalicylic acid to prevent any diliterious effects of the potent neurotoxin, MPP+, on mitochondrial function and superoxide anion generation, in vivo. Acetylsalicylic acid and acetaminophen prevented the MPP+-induced inhibition of the electron transport chain and complex I activity. In addition, acetylsalicylic acid and acetaminophen significantly attenuated the MPP+-induced superoxide anion generation. Furthermore the results provide novel data explaining the ability of these agents to prevent MPP+-induced mitochondrial dysfunction and subsequent reactive oxygen species generation. While these findings suggest the usefulness of non-narcotic analgesics in neuroprotective therapy in neurodegenerative diseases, acetylsalicylic acid appears to be a potential candidate in prophylactic as well as in adjuvant therapy in Parkinson's disease.



Protection against MPP+ neurotoxicity in cerebellar granule cells by antioxidants. - PubMed - NCBI
Protection against MPP+ neurotoxicity in cerebellar granule cells by antioxidants.
Abstract
The neuropathology associated with Parkinson's disease (PD) is thought to involve excessive production of free radicals, dopamine autoxidation, defects in glutathione peroxidase expression, attenuated levels of reduced glutathione, altered calcium homeostasis, excitotoxicity and genetic defects in mitochondrial complex I activity. While the neurotoxic mechanisms are vastly different for excitotoxins and 1-methyl-4-phenylpyridinium ion (MPP(+)), both are thought to involve free radical production, compromised mitochondrial activity and excessive lipid peroxidation. We show here that the levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) increased significantly after treatment of cultured cerebellar granule cells (CGCs) with 50 microM MPP(+). Co-treatment with antioxidants such as ascorbate (ASC), catalase, alpha-tocopherol (alpha-TOH), coenzyme Q(10) (CoQ(10)) or superoxide dismutase (SOD) rescued the cells from MPP(+)-induced death. MPP(+)-induced cell death was also abolished by co-treatment with nitric oxide synthase (NOS) inhibitors such as 7-nitroindazole (7-NI), 2-ethyl-2-thiopseudourea hydrobromide (EPTU) or S-methylisothiourea sulphate (MPTU). We also tested the protective effects of an iron chelator (deferoxamine mesylate, DFx) and a peroxynitrite scavenger (FeTTPS) and the results lend further support to the view that the free radical cytotoxicity plays an essential role in MPP(+)-induced death in primary cultures of CGC.

 

[haidut]

For the people that are worried about nicotinamide and PD - the study posted by the OP actually talks about how deficiency of niacinamide will produce PD. That deficiency is caused by overactivation of an enzyme that metabolizes niacinamide. The enzyme is known to be induced by stress and it is hypothesized (but not observed in practice yet) that increased exogenous niacinamide from supplements MAY also induce it. So, the only thing the study provides more or less for sure is that niacinamide deficiency induced by stress is tied to PD. So, whomever is worried about niacinamide, please the full study. Why longecity is raising alarm over this I am not sure, but I suppose they did not read the study very carefully.

"...High exposure to its substrates, particularly nicotinamide to which the Western population has become increasingly exposed may induce the enzyme, as will stress. This could be the first of several increasingly toxic vicious circles that result from the intra-neuronal deficiency of the vitamin or its downstream direct and indirect products, such as NADH and ATP combined with toxicity from several N-methylated compounds. If true, we are dealing with upstream events and switching them off would not just affect one part of a late cascade of biochemical events or be purely symptomatic, or be only aimed at the dopaminergic damage. Increased irreversible catabolism of nicotinamide may lead to the cellular deficiency of the vitamin and of products, which would also affect non-dopaminergic cells as seen in pellagra. Here dementia and depression are the predominant features, but autonomic, pontine, anosmic and sleep disturbances are seen, and remarkably, also parkinsonism in 10–20% of cases."

 

[High_Prob]

For the people that are worried about nicotinamide and PD - the study posted by the OP actually talks about how deficiency of niacinamide will produce PD. That deficiency is caused by overactivation of an enzyme that metabolizes niacinamide. The enzyme is known to be induced by stress and it is hypothesized (but not observed in practice yet) that increased exogenous niacinamide from supplements MAY also induce it. So, the only thing the study provides more or less for sure is that niacinamide deficiency induced by stress is tied to PD. So, whomever is worried about niacinamide, please the full study. Why longecity is raising alarm over this I am not sure, but I suppose they did not read the study very carefully.

"...High exposure to its substrates, particularly nicotinamide to which the Western population has become increasingly exposed may induce the enzyme, as will stress. This could be the first of several increasingly toxic vicious circles that result from the intra-neuronal deficiency of the vitamin or its downstream direct and indirect products, such as NADH and ATP combined with toxicity from several N-methylated compounds. If true, we are dealing with upstream events and switching them off would not just affect one part of a late cascade of biochemical events or be purely symptomatic, or be only aimed at the dopaminergic damage. Increased irreversible catabolism of nicotinamide may lead to the cellular deficiency of the vitamin and of products, which would also affect non-dopaminergic cells as seen in pellagra. Here dementia and depression are the predominant features, but autonomic, pontine, anosmic and sleep disturbances are seen, and remarkably, also parkinsonism in 10–20% of cases."

Perfect, thanks Haidut!

 

[Braveheart]

For the people that are worried about nicotinamide and PD - the study posted by the OP actually talks about how deficiency of niacinamide will produce PD. That deficiency is caused by overactivation of an enzyme that metabolizes niacinamide. The enzyme is known to be induced by stress and it is hypothesized (but not observed in practice yet) that increased exogenous niacinamide from supplements MAY also induce it. So, the only thing the study provides more or less for sure is that niacinamide deficiency induced by stress is tied to PD. So, whomever is worried about niacinamide, please the full study. Why longecity is raising alarm over this I am not sure, but I suppose they did not read the study very carefully.

"...High exposure to its substrates, particularly nicotinamide to which the Western population has become increasingly exposed may induce the enzyme, as will stress. This could be the first of several increasingly toxic vicious circles that result from the intra-neuronal deficiency of the vitamin or its downstream direct and indirect products, such as NADH and ATP combined with toxicity from several N-methylated compounds. If true, we are dealing with upstream events and switching them off would not just affect one part of a late cascade of biochemical events or be purely symptomatic, or be only aimed at the dopaminergic damage. Increased irreversible catabolism of nicotinamide may lead to the cellular deficiency of the vitamin and of products, which would also affect non-dopaminergic cells as seen in pellagra. Here dementia and depression are the predominant features, but autonomic, pontine, anosmic and sleep disturbances are seen, and remarkably, also parkinsonism in 10–20% of cases."

what would we do without you Mr Giorgi! Where did you study? Degree?

 

[haidut]

what would we do without you Mr Giorgi! Where did you study? Degree?

I am kind of like Ray - my academic "training" is in IT and I got into nutrition by accident. I worked as a bioinformatics researcher more than a decade ago and while it is still considered part of IT, I was working among people with biochemistry degrees. That spurred my interest, but I did not get into the biochem weeds until 2011 timeframe. Everything I know about it is through reading and experimenting. No formal training whatsoever, even tough I have a few doctor friends and we argue about medical stuff all the time. Not sure if that helps or just gives me grey hair

 

[Braveheart]

I am kind of like Ray - my academic "training" is in IT and I got into nutrition by accident. I worked as a bioinformatics researcher more than a decade ago and while it is still considered part of IT, I was working among people with biochemistry degrees. That spurred my interest, but I did not get into the biochem weeds until 2011 timeframe. Everything I know about it is through reading and experimenting. No formal training whatsoever, even tough I have a few doctor friends and we argue about medical stuff all the time. Not sure if that helps or just gives me grey hair :)

When you are truly interested in something, it spurs you on to learn all you can...and you become successful...let what you love become what you do.

 

[joaquin]

What if one uses niacinamide and that causes an upregulation of the enzyme that degrades it making it necessary to continue the use of NMN.