Thursday, February 21, 2013

Complex I, Hoffer and B3

Over the years I have read some pretty far out stuff. I think I've commented previously on the late Dr Abram Hoffer's use of B3 for controlling schizophrenia. Interesting and a source of thought trains which I never got the time to follow through. What I personally enjoyed were the accounts of recovered schizophrenics as to what it was like to have been inside the syndrome and then recover. Re-reading the site, it all looks very anecdotal now.

I also went so far as to purchase his book, written in conjunction with Linus Pauling, on treating cancer with vitamins B3 and C. You can just google the ISBN number 18970251141897025114 to find out a bit more about it. I see it's quite financially valuable nowadays!

Before we settle down to the nuts and bolts of the deeply involved models which the latest complex I paper (thanks George) used, the bottom line is that adding 1% nicotinamide (similar effects could be obtained with vitamin B3) to the mouse breast cancer models was very impressive at extending lifespan of those mouse models, especially through suppression of metastasis.

I find this slightly eerie. I can hear Hoffer in my head, sounding rational and being regarded as a quack for treating cancer (and many other illnesses including schizophrenia) with B3. Yet here are these guys in 2013 with their multiple mouse models, multiple tumour types, multiple interventions all showing that B3 or its analogue is very, very effective in suppressing breast cancer metastasis. In mouse models of course.

Slightly déjà vu...

A lot more to say about this paper but the B3 aspect is just so weird I had to put this aside up.

Peter

39 comments:

August said...

The other far out guy, Ray Peat, likes nicotinamide too.

Bill said...
This comment has been removed by the author.
Bill said...

Peter,
I don't know whether you are in communication with Dr. Art Ayers at http://coolinginflammation.blogspot.co.uk/ You should be. His blog is a mine of information and he is full of science as you are. Lay persons like me are in awe. The bottom line is that on a practical level you both talk sense. Even though most of the time the science loses me. Best wishes. Keep up the good work. I'm sure that 95%+ of your readers feel the same. I would add kisses but that would be gross!

George Henderson said...

The book that made me a Hoffer follower, and introduced me to B3, is The Hallucinogens written with Humphrey Osmond in 1966.

The concept is gobsmackingly awesome; Hoffer analyses - in comprehensive detail - a wide range of hallucinogens, and gives some of them to Osmond, who takes them and gives n=1 reports.
I'm not kidding, this is a gripping read. Osmond was probably the first person to ever trip on morning glory seeds, certainly the first American.
Niacin and ascorbic acid were his emergency comedown kit. He needed them in the final section, when he tried the adrenochrome he and Hoffer cooked up.

I am not making this up. (but re-reading it the reality is a little more complex than the remembered version I just gave)

In fact it's in the Erowid library.
http://www.erowid.org/library/books_online/hallucinogens_hoffer_osmond.pdf

"Since this was the first controlled
self-experiment by any psychiatrist,
one skillful in introspection and who had experienced the effects of
mescaline, LSD, adrenochrome, and adrenolutin, we will reproduce
verbatim this first scientific account [...]
When Osmond (1955) reported the results of the first psychiatric
self-experiment with ololiuqui, psychiatrists could not believe he was
correct for similar reasons and in addition for a more modern reason—
because it was a self-experiment and not done in what has since become the fashion in psychiatric research—the double blind experiment. In fact some have considered a self account no more and no less than a self
deception (see Kinross-Wright)."

I gave a megadose of B3 and C to someone who'd overdosed on magic mushrooms back in the day and was panicking, and it totally made things OK for him, met him hours later and he thanked me.

George Henderson said...

If you read the Hallucinogens, and I hope you do, one thing that will strike you is the references to glutathione and sulfhydryl groups, and to methylation as important factors in neurotransmitter balance and detoxification. This from the 1950-60s.

There is also a constant deferral to skepticism, there is no dressing of opinion or impressions as fact.

Hoffer pretty much abandoned clinical trials once it was obvious that patients benefited more from individualised, heuristic treatment.

But in his files will be the material for thousands of case studies.
Nowadays we would probably be able to produce some results via macronutrient ratios, minimizing toxins and optimising dietary nutrients and antioxidants, and thus might need lower doses of supplementary nutrients.

Niacinamide was recently found to help treat MRSA. It also has anti-TB activity (isoniazid was designed as a niacinamide analogue).

Kindke said...

Prefer nicotinic acid, the flush is too fun to miss!

ItsTheWooo said...

My grandmother was schizophrenic and ultimately died of breast cancer.

How ironic.

Maybe niacin defect?

My father is a grossly sane kook with anxiety and agitation and high blood pressure, so naturally I advised he take niacin and has been for quite awhile. I also have him taking D3 due to his not leaving the house and B1 due to his high alcohol diet.

I knew of niacin for BP but not for schizophrenia and cancer. Very interesting. Any idea how it works? Tried reading the site, just found anecdotes but no clear cut mechanisms.

Peter said...

I'll get round to B3 as a ketone mimetic, I mentioned it years ago. Increasing the NAD+ per unit NADH changes a sh!tload of downstream signalling in AKT etc, all the usual suspects. Like ketosis.

But we are still looking at a patch on complex I injury. Ketosis is probably the same patch.

The question is, what injures complex I in PD, AD, schizophrenia, obesity etc. Is it fixable? If it is the result of selecting for a certain mitochondrial type can we re select back for a better type? Or are we stuck with FADH2 from fat and a reduced inner mitochondrial membrane potential from ketones?

But my feeling is that complex I may well be where metabolic syndrome is at, so it's back to thinking about the usual suspects and how they fit together.

George: Ah, Erowid! Too grown up for psychonauting nowadays, maybe when the children are a bit more grown up!

Peter

George Henderson said...

@ Woo, I can understand mechanisms when niacinamide is effective; inhibiting IDO/TDO tryptophan breakdown = elevating serotonin and melatonin and lowering putatively neurotoxic tryptophan metabolites like kyneurenic acid; as methyl acceptor, slows down methylation of dopamine; and improving NAD+/NADH ratio has to help (mitochondrial dysfunction in schizophrenia).

Niacin, more difficult to understand why this would be more effective. It's a ketone receptor agonist, that's gotta be good, and releases prostagladin (PGE2 I think) for flush. So it messes with omega 6 inflammatory pathways. Mysteriously. It's a niacinamide precursor but also does its own thing.

The amount in diet is nowhere near supplement doses, and cancer rates probably haven't declined since bread was fortified, there's more in the food chain now than ever (although popularity of corn may be changing that).

We really are talking about a drug effect of a vitamin that's related to its natural role in some ways but not in others.
Niacinamide has been used as an adjunct in cancer to reduce cachexia.

Kindke said...

Peter,

I was under the impression that in obesity and weight gain there was an almost unanimous finding of elevated respiratory quotient indicative of excessive carbohydrate oxidation and therefore likely impaired fat oxidation. And that this in turn meant elevated activity of complex I.

bioenergetics really isnt my best subject but this is what I thought. But you say in obesity complex I in injured?

Ive never been so confused!

Bill said...

Come to think of it, I was at an EB conference about 5 years ago and attended a session about niacin binding to a "ketone receptor," but I haven't heard anything about it since... interesting.

Ned Kock said...

There are a lot of weird things about niacin Peter. Here is another one – it turbocharges the growth hormone response to anaerobic exercise, in a delayed way:

http://healthcorrelator.blogspot.com/search/label/niacin

Toxic said...

I like. Very much. "... the worst sin in orthodox medicine is to see a recovery for the wrong reason." Amen to that. I hope to commit the crime of niacin ingestion later in the week. I have already sinned by losing weight the wrong way, and by curing a raft of physical problems the wrong way. I just can't help myself. I am a very bad person.

When you cure your obesity the wrong way, doctors doubt you, even though they can read the scales. You have to lie to be taken seriously. I tried it out on the practice nurses. If you have lost weight, they always ask how you did it. If you say "low carb", they say HOW TERRIBLE and show you posters of pasta twirls. If you say "cutting down", they are full of praise and back slapping. They would rather you lost five pounds by starvation than five stones by low-carbing.

Thought it was very funny and ironic to read about doctors' self-experimentation with mind-bending drugs. Doctors today must be such wussies. How harmless is low carbing, compared to LSD?! You would think they might be curious and try out this crazy Atkins thing, before dismissing it. But they are terrified to try an egg, never mind a magic mushroom. One doctor I had spoke behind her hand and admitted she also low-carbed, but that no one in the practice must find out. I sat there open-mouthed at this. Low carb shame had forced her into the closet.

A couple of years ago I sat on a committee debating the management of a particular disease. The committee chairman was very eminent. In general chit chat, in a tea break, he refused a biscuit and started talking about how his wife had lost four stones and cured something or other (I think it was her arthritis) doing Atkins, and he had been absolutely amazed and mesmerised by this. He said he had become a total convert to low-carb. You could feel the room take in a sharp breath. Everybody (14 other specialists of varying types and two statisticians) TOTALLY ignored him and started chatting among themselves; asking nothing, volunteering nothing, withholding eye contact - cutting him stone dead. It was brutal. You could see he was very shaken. I started to agree with him wholeheartedly, but having only lost three stones by that point I had no power. You have to be very skinny to talk about weight in a room full of low carb denying doctors.

Ilaine Upton said...

Is ketosis, indeed, a patch, or did we all live in ketosis throughout human history until the holocene?

My guess is that we did.

Based on what hunter-gatherers actually ate. Where are the carbs? Some tubers, some grass grains. Hit or miss. It was all hit or miss. Mammals, reptiles, amphibians, fish, shellfish, insects, caterpillars, worms, tubers, grasses, broad leaved vegetation, whatever they could get.

dr j said...

here is an excellent work from Sydney Uni that sticks in my mind re NIM and skin cancer. Somewhere I have seen the photographs but for the life of me , I cant remember where!


Summary

Background  Ultraviolet (UV) radiation can profoundly suppress the cutaneous immune system, thus enhancing carcinogenesis. Agents that prevent UV-induced immunosuppression may thus reduce skin cancer. Nicotinamide (vitamin B3) prevents UV-induced immunosuppression and carcinogenesis in mice, and solar-simulated (ss) UV-induced immunosuppression in humans. Its effectiveness against different UV wavebands and mechanism of action is as yet unknown.

Objectives  To determine the effects and mechanisms of topical nicotinamide on UV-induced suppression of delayed type hypersensitivity (DTH) responses in humans.

Methods  Healthy Mantoux-positive volunteers in four randomised, double-blinded studies were irradiated with solar-simulated (ss)UV (UVB + UVA) or narrowband UVB (300 nm) or UVA (385 nm). Topical nicotinamide (0·2% or 5%) or its vehicle were applied immediately after each irradiation. Mantoux testing was performed at irradiated sites and adjacent unirradiated control sites 48 h after the first irradiation and measured 72 h later. Immunosuppression was calculated as the difference in Mantoux-induced erythema and induration at test sites compared to control sites. Human keratinocyte cell cultures, with and without ssUV and nicotinamide, were used for quantitative real-time reverse transcriptase-polymerase chain reaction assessment of TP53 and enzymes that regulate oxidative phosphorylation.

Results  Nicotinamide cooperated with ssUV to increase enzymes involved in cellular energy metabolism and p53, and significantly protected against immunosuppression caused by UVB, longwave UVA and single and repeated ssUV exposures.

Conclusions  Longwave UVA, which is poorly filtered by most sunscreens, was highly immune suppressive even at doses equivalent to 20 min of sun exposure. Nicotinamide, which protected against both UVB and UVA, is a promising agent for skin cancer prevention.

dr j said...

http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2133.2009.09244.x/abstract
sorry!

dr j said...

here is an ahead of print abstract

Carcinogenesis. 2013 Feb 13. [Epub ahead of print]
Nicotinamide enhances repair of ultraviolet radiation-induced DNA damage in human keratinocytes and ex vivo skin.
Surjana D, Halliday GM, Damian DL.
Source

Department of Dermatology, Sydney Cancer Centre, Bosch Institute, University of Sydney at Royal Prince Alfred Hospital, Camperdown, Sydney, NSW 2006, Australia.
Abstract

Nicotinamide (vitamin B3) protects from ultraviolet (UV) radiation-induced carcinogenesis in mice and from UV-induced immunosuppression in mice and humans. Recent double-blinded randomized controlled Phase 2 studies in heavily sun-damaged individuals have shown that oral nicotinamide significantly reduces premalignant actinic keratoses, and may reduce new non-melanoma skin cancers. Nicotinamide is a precursor of nicotinamide adenine dinucleotide (NAD(+)), an essential coenzyme in adenosine triphosphate (ATP) production. Previously, we showed that nicotinamide prevents UV-induced ATP decline in HaCaT keratinocytes. Energy-dependent DNA repair is a key determinant of cellular survival after exposure to DNA-damaging agents such as UV radiation. Hence, in this study we investigated whether nicotinamide protection from cellular energy loss influences DNA repair. We treated HaCaT keratinocytes with nicotinamide and exposed them to low-dose solar-simulated UV (ssUV). Excision repair was quantified using an assay of unscheduled DNA synthesis. Nicotinamide increased both the proportion of cells undergoing excision repair and the repair rate in each cell. We then investigated ssUV-induced cyclobutane pyrimidine dimers (CPDs) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8oxoG) formation and repair by comet assay in keratinocytes and with immunohistochemistry in human skin. Nicotinamide reduced CPDs and 8oxoG in both models and the reduction appeared to be due to enhancement of DNA repair. These results show that nicotinamide enhances two different pathways for repair of UV-induced photolesions, supporting nicotinamide's potential as an inexpensive, convenient and non-toxic agent for skin cancer chemoprevention.

George Henderson said...

Toxic,
in this pyridoxine neurotoxicity study the 5 authors were the 5 volunteers
http://www.neurology.org/content/42/7/1367.short

I always admire that stuff.

@ Ilaine, full-time ketosis was probably not a default except in permafrost latitudes, but intermittent ketosis, certainly.
This account from the Andaman Islands seems fully ancestral to me:
http://www.andaman.org/BOOK/chapter15/text15.htm

"In a simple society, food is the main source of the joy and excitement that makes life worth living. The absence of food means hunger and depression, its presence happiness and elation. Food cannot not be stored for more than a day or two. Every day is a new gamble and famine is never far away.

The amount of fatty meat consumed daily during the rainy season when pork was at its fattest was large and could on occasions rise to the truly gargantuan. People with an average adult body weight of around 40 kg (88 lb.) could, on occasion, eat up to 1.8 kg (4 lb.) of food. This could rise to a staggering 4.5 kg (10 lb.) during a 24-hour period on special occasions. At major feasts , during colossal honey-and-pork orgies, participants stuffed themselves to bursting point, leaving everyone barely able to walk and with severe indigestion for days.

A diet rich in animal fats together with the occasional over-indulgence cried out for a counter-balance in the form of starchy roots, vegetables and fruit. These were available throughout the year but most abundant during the dry season. Gathering the unglamorous but necessary supplements was left to the women."

These islanders not only practice no agriculture, they cut down all the coconut trees on the islands long ago.

Taka said...

This may have to do something with Dopamine. Most of us are infected with a brain parasite (especially cat owners) which overproduces dopamine in our brains (Toxoplasma gondii). This puts us into the high gear "psychotic" breeding mode (like the old days Coca Cola with cocaine) with side effects such as the breast cancer. Now B3 has been reported to cause dopamine-deficient phenotype, anybody home?

http://www.ncbi.nlm.nih.gov/pubmed/19539713

Peter said...

Kindke,

I think normal pre obese people run metabolism on carbohydrate because fat is being sequestered/locked in to adipocytes and while ever this happens they remain insulin sensitive, with low FFAs and a high RQ. They have to eat to maintain an adequate metabolic milieu for normal function. Once they have insulin resistance in their adipocytes they can get back to normal function due to increased FFAs and have no ability/need to gain weight but they do have problems post (carb) prandially due to hyperglycaemia from FFA induced insulin resistance of course. The point of interest is why they have over insulin sensitive adipocytes in the first place. I'm thinking omega 6 fats here.

The cancer cells are utterly broken and have a severe complex I deficiency and so run on glycolysis with very restricted ox phos. In an entire organism they would develop elevated lactic acid and rely on liver function to live with this. This does happen and lactic acidosis is a marker of glycolytic tumours.

I would stress that these are cancer cells showing the Warburg effect and this is by no means ubiquitous in cancer metabolism. There are many types of cancer which have highly functional mitochondria. Life is not always simple.

To me the question is how the transition occurs from weight gain with limited metabolic damage to a fully mangled complex I in a cancer cell. There is no doubt that metabolic syndrome is associated with multiple cancer types (probably the ones which show the Warburg effect) so I suspect there is a progression here.

Nice query.

The next question is whether it is the break in complex I which triggers the aggressive phenotype due to low NAD+/NADH ratio or whether the abnormal ratio is what generates the break in the first place. Then we are back to the consequences of FAILING to generate insulin resistance when there is a ton of ATP available and the NADH isn't going anywhere because the ETC is backed up.

Also you have to throw in the offspring of diabetic parents who appear to have been born with abnormal mitochondria. Then you are back to mitochondrial bottlenecks in foetal development and mitochondrial protection in oocytes. And the usual suspects of course.

Peter

Jane said...

Peter says 'The question is, what injures complex I in PD, AD, schizophrenia, obesity etc.'

Yes, that's what we need to know. It looks like complex 1 is not properly assembled.

'Parkinson's Disease Brain Mitochondrial Complex I Has Oxidatively Damaged Subunits and Is Functionally Impaired and Misassembled'
http://www.jneurosci.org/content/26/19/5256.short

Most interestingly, assembly appears to require methylation, which is important in Alzheimer's.
'[Assembly factor] C20orf7 also has a predicted S-adenosylmethionine-dependent methyltransferase (SAM) domain, and this may be important for its function—potentially through the direct methylation of complex I subunits.'
'Assembly factors of human mitochondrial complex I and their defects in disease'
http://onlinelibrary.wiley.com/doi/10.1002/iub.335/full

And methylation is impaired in PD patients.
'Markers of neurodegeneration (APP, alpha-synuclein) are related to markers of methylation (SAM, SAH) in patients with PD. Better cognitive function was related to higher methylation potential (SAM/SAH ratio).'
'Methylation status and neurodegenerative markers in Parkinson disease'
http://www.ncbi.nlm.nih.gov/pubmed/19679632

George Henderson said...

Here's where I'd refer back to Aubrey de Grey's mitochondrial papers. He's all about reductive stress (NAD+/NADH) and the mechanisms that cause mitochondrial mutation in aging.
The old mitochondrial theory (which Grey disputes in aging) is that accidental generation of ROS damages mito dNA over time.
But Jane suggests a different mechanism, that mito ROS inhibit methylation.
Peroxynitrite will bind to hydroxycobalamin, B12 is vulnerable to oxidative stress and is recycled by glutathione.

donny said...

http://www.ncbi.nlm.nih.gov/pubmed/19095763
----------------------
Abstract
Serotonin (5-HT) regulates peristaltic and secretory reflexes in the gut. The serotonin reuptake transporter (SERT; SLC6A4), which inactivates 5-HT, is expressed in the intestinal mucosa and the enteric nervous system. Stool water content is increased and colonic motility is irregular in mice with a targeted deletion of SERT. We tested the hypotheses that 5-HT plays a role in regulating intestinal inflammation and that the potentiation of serotonergic signaling that results from SERT deletion is proinflammatory. Rectal installation of 2,4,6-trinitrobenzene sulfonic acid (TNBS) was used to induce an immune-mediated colitis, which was compared in SERT knockout mice and littermate controls. Intestinal myeloperoxidase and histamine levels were significantly increased, whereas the survival rate and state of health were significantly decreased in TNBS-treated mice that lacked SERT. Deletion of SERT thus increases the severity of TNBS colitis. These data suggest that 5-HT and its SERT-mediated termination play roles in intestinal immune/inflammatory responses in mice.
-------------------------
All sorts of connections here... maybe a connection to celiac disease being associated with schizophrenia? A lot of neurotransmitters have less glamorous roles in the intestine... Mess up serotonin globally, and you don't just expect mental issues, ability to handle assaults on the gut might be reduced as well. I've seen a lot of stuff lately about how the immune system is involved in brain development... which makes sense. I'm starting to think of immune cells as environment generators--cells develop largely according to their environment, and it's effects on their genetic expression, immune cells do a lot to change the local environment. So mess up the gut... mess up the immune system... mess up cell expression etc. Really mess up the brain?

Lots of gut issues, celiac and some schizophrenia in my family. Including acute schizophrenia that just sort of (mostly) went away in myself. Although I should probably switch my self-diagnosis to bipolar, since I did have that one manic episode. I prefer to separate the two and be both, and neither.

karl said...

When I started digging into CAD I was surprised that many of the possible dietary interventions were also used to treat depression ( vit-D, low-carb, niacin etc.. )

There are several lines of evidence that have led me to believe that much of mental illness may actually be caused by the immune system.

Various antidepressants reduce cytokines and inflammatory interleukins ( and thus may not actually work via the accepted catecholamine explanation! ).

Ask anyone that has undergone interferon treatment for hepatitis - the depression is serious. http://www.ncbi.nlm.nih.gov/pubmed/18079286

What if much of mental illness is really just cytokines - effecting people in ways that are not understood?

Ketamine, a animal anesthetic, has been found to quickly relive depression - it also is used to reduce post surgical inflammation. ( a few links : http://wiki.xtronics.com/index.php/Interventions_for_Preventative_Heart_Health#Ketamine_.3F.3F )

Peter said...

karl,

I would view this the other way round, there are a whole host of problems with an associated NAD+/NADH ratio problems, ie with energy supply. In particular the crashing depression associated with hypothyroidism always comes to mind.

Ketamine is an NMDA antagonist and will have a whole stack of bioenergetic effects through blocking Ca2+ influx in to cells under glutamate agonists. Some cells are more up for death from glutamate agonists than others. One of the arguments against using Ca2+ infusions for CV support in horses come from the potentially lethal effects of Ca2+ elevation on cells under physiological stress. A pity, a bottle of cow calcium borogluconate was a whole stack easier to use than a dobutamine infusion for cardiovascular support. You could almost run the b*ggers by eye, no infusion pump needed. Seemed to work pretty well too.

Life is much easier if you don't have to gas horses for a living!

Peter

Jane said...

@George
'But Jane suggests a different mechanism, that mito ROS inhibit methylation.'

No, I'm not suggesting that. I'm suggesting complex I is not properly assembled, and makes ROS because electron flow is disturbed due to the misassembly. Methylation seems to be needed for assembly, but would not be inhibited by the ROS - remember this is complex 1 being assembled, before it's functional - but by B vitamin deficiency or other deficiencies.

In Alzheimer's it's been found that brain shrinkage can be prevented by high doses of B vitamins. The relevant vitamin seems to be B12, but you need a really enormous dose. Probably because the enzyme B12 activates, methionine synthase, also requires copper. Actually the whole methylation pathway seems to be dependent on copper, because methylation reactions are prevented by S-adenosylhomocysteine, which is broken down by the copper enzyme SAH hydrolase.

I have been trying to tell the scientists who did the study on brain shrinkage and B vitamins about copper for years. Copper is inconvenient, I suppose.

karl said...

@ Peter
"associated NAD+/NADH ratio problems,"

It seem it really could be that NAD+/NADH ratio problems trigger (or is the basis of) some kind of immune response - we are getting into the mechanism that triggers cell death and senescence cells also leak interleukins.. Sure wish I could fast-forward the science to see how this plays out.

George Henderson said...

@ Jane,
suggests to me, I mean. If methylation is required for complex 1 completion and B12 is vulnerable to oxidative stress then we don't need ROS causing mutation in mito DNA for it to screw up complex 1, and this gets around any objections about whether mito DNA mutations are always the cause of malfunction.

@ Karl, interferon upregulates indolamine or tryptophan deoxygenase and depletes tryptophan down NAD+ synthetic pathway.
Ribavirin inhibits tetrahydrobiopterin, an unusual little co-enzyme required for synthesis of both serotonin and tyrosine.

@ Donny, makes sense to me. Interferon sensitises gut dendrite cells to gluten; there is a gluten sensitivity of viral illness.

Jane said...

@George
Yes exactly. ROS-dependent mito DNA damage is certainly important, but not essential to explain complex 1 malfunction. I think methylation and its need for copper can explain a lot. You know there are doctors who are finding that what they thought was B12 deficiency is actually copper deficiency.

'Unrecognized copper deficiency appears to be a common cause of idiopathic myelopathy in adults. The clinical picture bears striking similarities to the syndrome of subacute combined degeneration associated with vitamin B12 deficiency. ..'
http://www.neurology.org/content/63/1/33.abstract?ijkey=a7d9e23232c4633d422b27cfcfa292619d66fa24&keytype2=tf_ipsecsha

Not surprising if the enzyme that needs B12 also needs copper. B12 deficiency is difficult to explain but copper deficiency is not.

And look at this: 'Copper deficiency myeloneuropathy due to occult celiac disease'
http://www.ncbi.nlm.nih.gov/pubmed/19901719

The very same syndrome in celiac disease. Does this mean celiac causes copper deficiency, or might it mean copper deficiency causes celiac? After all, the problem in celiac is a malfunctioning immune system, and we know the immune system is very sensitive to copper deficiency. The Linus Pauling Institute tells us 'Copper is known to play an important role in the development and maintenance of immune system function, but the exact mechanism of its action is not yet known. ..'
http://lpi.oregonstate.edu/infocenter/minerals/copper/

Makro said...

Interesting:

http://kindkehealthnotes.blogspot.se/2013/02/muscle-fat-oxidation-fat-people-vs-lean.html

mark said...

What do you think of the papers below? Could niacin might create PD risk? Could it be avoided by taking vitamin C or other supplement? Thanks.

http://qjmed.oxfordjournals.org/content/98/3/215.full

Parkinson's disease: the first common neurological disease due to auto-intoxication?
A.C. Williams1, L.S. Cartwright2 and D.B. Ramsden2
From the Divisions of 1Neurosciences and 2Medical Sciences, University of Birmingham, Birmingham, UK

Parkinson's disease may be a disease of autointoxication. N-methylated pyridines (e.g. MPP+) are well-established dopaminergic toxins, and the xenobiotic enzyme nicotinamide N-methyltransferase (NNMT) can convert pyridines such as 4-phenylpyridine into MPP+, using S-adenosyl methionine (SAM) as the methyl donor. NNMT has recently been shown to be present in the human brain, a necessity for neurotoxicity, because charged compounds cannot cross the blood-brain barrier. Moreover, it is present in increased concentration in parkinsonian brain. This increase may be part genetic predisposition, and part induction, by excessive exposure to its substrates (particularly nicotinamide) or stress. Elevated enzymic activity would increase MPP+-like compounds such as N-methyl nicotinamide at the same time as decreasing intraneuronal nicotinamide, a neuroprotectant at several levels, creating multiple hits, because Complex 1 would be poisoned and be starved of its major substrate NADH. Developing xenobiotic enzyme inhibitors of NNMT for individuals, or dietary modification for the whole population, could be an important change in thinking on primary and secondary prevention.


http://www.jstage.jst.go.jp/article/ehpm/10/1/10_3/_article

Niacin Metabolism and Parkinson’s Disease

Epidemiological surveys suggest an important role for niacin in the causes of Parkinson’s disease, in that niacin deficiency, the nutritional condition that causes pellagra, appears to protect against Parkinson’s disease. Absorbed niacin is used in the synthesis of nicotinamide adenine dinucleotide (NAD) in the body, and in the metabolic process NAD releases nicotinamide by poly(ADP-ribosyl)ation, the activation of which has been reported to mediate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson’s disease. Recently nicotinamide N-methyltransferase (EC2.1.1.1) activity has been discovered in the human brain, and the released nicotinamide may be methylated to 1-methylnicotinamide (MNA), via this enzyme, in the brain. A deficiency in mitochondrial NADH:ubiquinone oxidoreductase (complex I) activity is believed to be a critical factor in the development of Parkinson’s disease. MNA has been found to destroy several subunits of cerebral complex I, leading to the suggestion that MNA is concerned in the pathogenesis of Parkinson’s disease. Based on these findings, it is hypothesized that niacin is a causal substance in the development of Parkinson’s disease through the following processes: NAD produced from niacin releases nicotinamide via poly(ADP-ribosyl)ation, activated by the hydroxyl radical. Released excess nicotinamide is methylated to MNA in the cytoplasm, and superoxides formed by MNA via complex I destroy complex I subunits directly, or indirectly via mitochondrial DNA damage. Hereditary or environmental factors may cause acceleration of this cycle, resulting in neuronal death.

Jeffrey of Troy said...

COPPER

Carl Pfeiffer thought that some schizophrenics needed much more copper than the avg person, other schizophrenics much less copper than avg. (Perhaps the two extreme ends of the continuum of rate at which copper is metabolized?)

NIACIN MECHANISM

My understanding of Hoffer (and Osmond)'s understanding of why B3 at multi gram doses worked for schizos is that everyone produces adrenochrome as a highly toxic waste product, but in normal people it is broken down and eliminated w/o consequence. In schizophrenia, the person's brain makes the adrenochrome, but fails to break it down; the large quantity of B3 "mops up" the adrenochrome. (I am not a chemist or doctor.)

http://www.alternativementalhealth.com/articles/nutritionschizophrenia.htm

I haven't read this study, but seems relevant:
http://www.orthomolecular.org/library/jom/1999/articles/1999-v14n01-p028.shtml

George Henderson said...

@ Mark, no.
This effect is a product of the NADH/NAD+ excess; the complex 1 injury is the causative factor (once again). Compounds that generate superoxide such as paraquat can cause PD.
Those papers are looking, I think, at an adaptive mechanism that helps deal with complex 1 inhibition in PD and calling it a smoking gun.
If it was correct there would be high rates of PD in people using niacin but there are no correlations i know of and this study discounts the theory:

http://onlinelibrary.wiley.com/doi/10.1002/1531-8257(199901)14:1%3C28::AID-MDS1007%3E3.0.CO;2-O/abstract

Nutritional and occupational factors influencing the risk of Parkinson's disease: A case-control study in southeastern Sweden

To investigate the possible impact of nutritional and environmental risk factors for idiopathic Parkinson's disease (IP), a case-control study was performed in the county of Östergötland in southeastern Sweden. The study involved 113 cases of IP and 263 control subjects. Dietary, drinking, and smoking habits, as well as previous occupation, were requested in a structured questionnaire.

RESULTS
No increased risk was found for any of the nutritional items in which information was requested. A reduced risk was found for coffee, wine, and liquor at various consumption levels but also for fried or broiled meat, smoked ham or meat, eggs, French loaf or white bread, and tomatoes. All these food and drink items contain niacin. As in many studies, the frequency of preceding and present smoking was reduced in IP patients.

Various occupational groups and exposures were analyzed and increased risks of IP in men were found for agricultural work along with pesticide exposure; this was also the case for male carpenters and female cleaners.

CONCLUSIONS
The findings indicate that nutritional factors and occupational exposures, especially to pesticides, could be of etiologic importance in IP.

blogblog said...

@Dr J,

Australia has he world's highest level of skin cancers. However 70% of Australians are vitamin D deficient.

The main problem is that we Australians tend to get a lot of sun exposure on a small skin area (face and hands) - rather than a exposing a large skin area for a short time.

mark said...

@George Henderson
Thank you. I was thinking of not dietary niacin, but supplemental niacin many people take at high doses such as 1-4g/d for improving blood lipids. I agree with you that if it had PD risk, they would have noticed some correlation in many long term niacin trials where high doses were given to patients. However, in those trials maybe the patients were not given also methyl donors, whereas many people take it with various methyl donors now, as it became clear that niacin is a methyl sponge and these papers seem to link PD risk with methyl donors, such as SAMe.
Thanks again.

George Henderson said...

@ Mark,
they seem to be saying that niacin deficiency protects against PD, but this necessarily isn't the same thing as saying that niacin will aggravate it. Thiamine deficiency will protect against weight gain, but thiamine repletion just allows a normal response to excess carbohydrate.
Niacin deficiency would mean less NADH to feed to complex 1 to begin with so fewer ROS.
I think the methyl acceptor effect of niacin can account for cases of hepatotoxicity; it would tend to inhibit choline synthesis at very high intakes.
The question is whether N-methylnicotinamide could ever accumulate in brain at a level to produce complex 1 inhibition and whether effect this could ever match that of the toxins more directly linked to PD.
Also, if NMNA was not being formed, what would happen?

Mitochondrial Complex I Deficiency in Parkinson's Disease

http://onlinelibrary.wiley.com/doi/10.1111/j.1471-4159.1990.tb02325.x/abstract;jsessionid=2BC8215D714FF61D38E44BF681BD5CDC.d01t04?deniedAccessCustomisedMessage=&userIsAuthenticated=false

Abstract: The structure and function of mitochondrial respiratory-chain enzyme proteins were studied postmortem in the substantia nigra of nine patients with Parkinson's disease and nine matched controls. Total protein and mitochondrial mass were similar in the two groups. NADH-ubiquinone reductase (Complex I) and NADH cytochrome c reductase activities were significantly reduced, whereas succinate cytochrome c reductase activity was normal. These results indicated a specific defect of Complex I activity in the substantia nigra of patients with Parkinson's disease. This biochemical defect is the same as that produced in animal models of parkinsonism by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and adds further support to the proposition that Parkinson's disease may be due to an environmental toxin with action(s) similar to those of MPTP.

George Henderson said...

While MPTP itself has no psychoactive effects, the compound may be accidentally produced during the manufacture of MPPP, a synthetic opioid drug with effects similar to those of morphine and pethidine (meperidine). The Parkinson-inducing effects of MPTP were first discovered following accidental ingestion as a result of contaminated MPPP.

http://en.wikipedia.org/wiki/MPPP

Jane said...

Jeffrey of Troy said...
'COPPER
Carl Pfeiffer thought that some schizophrenics needed much more copper than the avg person, other schizophrenics much less copper than avg. ..'

Yes, some had high serum copper and he thought they had copper overload. However, high serum copper does not mean copper overload, it means inflammation. We know now that schizophrenia is accompanied by inflammation.
'Inflammation in schizophrenia'
http://www.ncbi.nlm.nih.gov/pubmed/22814706
'Growing evidence from clinical studies with COX-2 inhibitors points to favorable effects of anti-inflammatory therapy in schizophrenia...'

As it happens there is a natural endogenous inhibitor of COX-2, and it's ... copper.
'Sensitive, Selective, and Irreversible Inhibition of Cyclooxygenase-2 Activity by Copper'
http://www.ncbi.nlm.nih.gov/pubmed/18000939

So it looks like both groups of Pfeiffer's schizophrenic patients might have had copper deficiency.

George Henderson said...

@) Jane,

Copper (as ceruloplasmin) is increased in acute phase inflammation and is reduced by homocysteine (also elevated at site by higher phospholipid turnover from production prostaglandins) to produce hydroxyl radical from superoxide via Fenton reaction.

@ Peter, Mark,
the NAD/NADH balance links in to inflammation thusly:
Complex 1 is munted in some way, and one way of relieving the reductive stress (not enough NAD+) is supplying extra NAD+ from tryptophan degradation.
Trytophan degredation will stimulate an anti-inflammatory mechanism, Treg/Th17 differentiation.

Another is (at least in theory) sacrificing methyl groups to remove H from NADH (creating methane and NAD+). This might exacerbate the hypomethylation of Complex 1, as might the methylation of Nicotinamide itself.

Increasing methyl-nicotinamide can also increase nicotinamide levels in glioma: http://www.ncbi.nlm.nih.gov/pubmed/20495288

http://www.ncbi.nlm.nih.gov/pubmed/16704296

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC329730/pdf/jcinvest00484-0141.pdf

I can't make sense of this; but perhaps factoring in the mitochondrial functioning in each condition explains it. The only conclusion so far is that interferon-gamma influences redox balance by this mechanism, and that there is a feedback loop by which this process is anti-inflammatory.

Which is why nicotinamide is a potent anti-inflammatory - in nature it is a product of adaptive inflammation and higher levels become a signal to desist.

For example,
http://www.ncbi.nlm.nih.gov/pubmed/16704296

Nicotinamide caused decreased spontaneous (p = 0.05) and in vitro autoantigen-induced IFN-gamma secretion (p < 0.05) and may play a role in immune regulation, even though it has not been shown to prevent T1D.