By Dr. Malcolm Kendrick | December 6, 2021
Here I am on vitamins again. I don’t wish to give the impression that all I care about is vitamins. However, I have been thinking about them recently for various reasons.
The first thing to say is that I do find it slightly strange that we have substances which are absolutely essential for life, that we must eat., because our bodies cannot make them. It seems a design flaw. I want my money back.
Added to this absolute reliance on them, we do not get any hint that we are running out. If we become dehydrated, we feel thirsty, and we drink. If our energy supplies are running down, we feel hungry and we eat.
On the other hand, if our Vitamin B12 supplies are becoming perilously low – we might end up feeling bloody awful. In the final stages we could end up paralyzed, then dead, without knowing why. Vitamin B12 is essential for the health of neurones (amongst other things). But there is nothing that triggers our desire to forage around for foodstuffs rich in vitamin B12. Supposing we knew what they were anyway.
I presume this means that whilst we were evolving from the primeval soup, there were plenty of vitamins (and minerals) about. We had no need to seek them out specifically, because they were always present in the things we ate. In ample supply? Always …? Of course, it is not just vitamins, there are minerals we need too.
Magnesium
Most people are probably blissfully unaware they need magnesium. If you don’t have enough, how would you know? The first recognisable symptom may be … suddenly dropping dead.
Israel gives us a stark warning of what happens when magnesium goes missing, with no-one noticing. For many years, most of the water supply in Israel has been provided by desalination. This process does not just get rid of salt (NaCl), it also removes the other salts, and minerals, at the same time.
In normal circumstances people get most of the magnesium they need from drinking water. Which means there was clearly a potential for a major deficiency problem building up in Israel. As most of their water contained nothing but pure H20.
Did anyone notice? As in, did anyone say, ‘golly I feel low in magnesium today, I must go and eat a substance high in magnesium…’ Nope. Did anyone die. Yup, they did. As outlined in the paper ‘Association between exposure to desalinated sea water and ischemic heart disease, diabetes mellitus and colorectal cancer; A population-based study in Israel.’ 1
There were possibly as many as 4,000 deaths a year:
‘An estimated 4,000 Israelis die in an average year due to an inadequate amount of magnesium in their bodies – and the amount they get from natural potable water sources is increasingly declining due to the growing desalination of sea water. The figure is 10-fold the death toll from road accidents.’ 2
The population of Israel is just over nine million. The equivalent death rate in the UK would be 30,000 deaths a year, or 180,000 in the US. A silent killer indeed.
Anyway, yes, magnesium is critical stuff. It is extremely important for health, especially heart health. It is required for the correct functioning of the electrical system in your heart, and a low level increases the risk of atrial fibrillation. Here from the paper ‘Low serum magnesium and the development of atrial fibrillation in the community: the Framingham Heart Study.’
‘… individuals in the lowest quartile of serum magnesium were ~50% more likely to develop AF…compared with those in the upper quartiles.’ 3
Unfortunately, despite its importance, we don’t feel magnesium depleted. We do not crave magnesium rich foods – as if we would have any idea what they might be … I certainly don’t. The symptoms of severe deficiency are also non-specific. The first symptom might be that your heart decides to stop beating.
It’s not just Israel. Here from the paper: ‘Subclinical magnesium deficiency: a principal driver of cardiovascular disease and a public health crisis.’
‘Furthermore, because of chronic diseases, medications, decreases in food crop magnesium contents, and the availability of refined and processed foods, the vast majority of people in modern societies are at risk for magnesium deficiency.’ 4
Have you ever heard of any of this? Did you even know you had magnesium in your body – or that it did anything important? I suspect not. However, from the same paper:
‘… magnesium deficiency can lead to serious morbidity and mortality and has been implicated in multiple cardiovascular diseases such as hypertension, cardiomyopathy, cardiac arrhythmia, atherosclerosis, dyslipidaemia and diabetes. Unfortunately, the western diet is often low in magnesium due to the refining and processing of foods, and hypomagnesaemia is often underdiagnosed in hospitalised patients.’4
My advice, take a supplement. Especially if you live in an area with ‘soft’ water – which generally means not many minerals. Doubly especially if you have atrial fibrillation. It might just go away. How much do you need to take? Around 400mg a day is fine.
Back to vitamins – in this case, Vitamin(s) B
The reason for the detour is that I really wanted to make it clear that it is certainly not a given that we routinely get all the essential micro-nutrients we need from our diet.
Modern living, modern food production and farming, modern food processing … have all have a significant impact on what our food, and water, contains.
The lazy mainstream assumption that micronutrient deficiencies simply do not exist is, therefore, wrong. Try looking at Iodine deficiency in Switzerland sometime. In addition, I am extremely dubious that we truly know what the optimal intake of micronutrients may be. The research in this area is sketchy, to say the least.
This, eventually, takes us onto vitamins, more specifically, the B vitamins. There are many of them – eight, in fact.
B1 (thiamine)
B2 (riboflavin)
B3 (niacin)
B5 (pantothenic acid)
B6 (pyridoxine)
B7 (biotin)
B9 (folate aka folic acid)
B12 (cobalamin)
The first question that springs to mind is the following. Where are numbers four, eight, ten and eleven? What happened to them? It’s a bit like clotting factors. We have VII, VIII, IX etc. But there is no factor one, or two. Who gets to name things in medicine anyway?
Moving on. My main interest in the B vitamins is that, if you are low in three of them, maybe four of them: three, six, nine and twelve, this can lead to an increased level of a protein in the blood called homocysteine. [I think B6 is more important than B3, but we shall let this go for now].
The reason why this is important is if you have a high level of homocysteine then this is strongly associated with an increased risk of cardiovascular disease. The mechanism of action appears to be that homocysteine is toxic to endothelial cells.
‘Elevated homocysteine (Hc) levels have a well-established and clear causal relationship to epithelial damage leading to coronary artery disease.’ 5
On the other hand, low levels of homocysteine are associated with a lower risk:
‘In observational studies, lower homocysteine levels are associated with lower rates of coronary heart disease and stroke. Folic acid and vitamins B6 and B12 lower homocysteine levels.’[i]
As you may have gathered from that short quote, if you have a high homocysteine level, and you take B vitamins, your homocysteine levels will fall. As confirmed in a study in the American Journal of Clinical Nutrition :
‘Elevated levels of homocysteine is an indication of inadequate folate and vitamin B-12 in the diet, writes lead author Giovanni Ravaglia, a researcher with University Hospital S. Orsola-Malpighi in Bologna, Italy. His paper appears in the March American Journal of Clinical Nutrition….High homocysteine levels can be treated very easily with vitamins, including folate, niacin, and B-12.’ 6
I think the connection between B vitamins, and homocysteine, were first noted by Kilmer McCully. He studied the area in detail at Harvard University. At least he did so for a while, before he was unceremoniously booted out for carrying out research that threatened to undermine the almighty cholesterol hypothesis. A sorry tale, as reported in the New York Times :
‘Thomas N. James, a cardiologist and president of the University of Texas Medical Branch who was also the president of the American Heart Association in 1979 and ’80, is even harsher [regarding the treatment of McCully]. ”It was worse than that you couldn’t get ideas funded that went in other directions than cholesterol,” he says. ”You were intentionally discouraged from pursuing alternative questions. I’ve never dealt with a subject in my life that elicited such an immediate hostile response.”
It took two years for McCully to find a new research job. His children were reaching college age; he and his wife refinanced their house and borrowed from her parents. McCully says that his job search developed a pattern: he would hear of an opening, go for interviews and then the process would grind to a stop. Finally, he heard rumors of what he calls ”poison phone calls” from Harvard. ”It smelled to high heaven,” he says.’
McCully says that when he was interviewed on Canadian television after he left Harvard, he received a call from the public-affairs director of Mass. General. ”He told me to shut up,” McCully recalls. ”He said he didn’t want the names of Harvard and Mass. General associated with my theories.’ 7
And you wonder why researchers are wary of questioning the cholesterol hypothesis? Yes, crushing scientific debate has a long and inglorious history, starting long before COVID19 first appeared over the horizon. In the world of cholesterol, it has been going on for well over sixty years.
Homocysteine, B vitamins and dementia
Now, dear reader, having just focussed on B vitamins, homocysteine and cardiovascular disease, I am going to abruptly change tack. I shall now move away from heart disease to Alzheimer’s disease. The reason for this is straightforward.
As I began to research this area in more detail, it became increasingly clear that there was a worrying association between raised homocysteine, brain damage, and dementia. This certainly attracted my attention. Because I like my brain, and I want to keep it healthy for as long as possible.
I came across papers such as this: ‘Plasma Homocysteine as a Risk Factor for Dementia and Alzheimer’s Disease.’
‘An increased plasma homocysteine level is a strong, independent risk factor for the development of dementia and Alzheimer’s disease.’ 8
There were many more such papers, but you probably get the general idea. Raised homocysteine … Bad.
At this point I already knew that the B vitamins can lower the homocysteine level – if it is high. In addition, B vitamins are well known to have vital functions in the central and peripheral nervous system.
Here, from the paper: ‘B Vitamins in the nervous system: Current knowledge of the biochemical modes of action and synergies of thiamine, pyridoxine, and cobalamin.’
Neurotropic B vitamins play crucial roles as coenzymes and beyond in the nervous system. Particularly vitamin B1 (thiamine), B6 (pyridoxine), and B12 (cobalamin) contribute essentially to the maintenance of a healthy nervous system. Their importance is highlighted by many neurological diseases related to deficiencies in one or more of these vitamins, but they can improve certain neurological conditions even without a (proven) deficiency.’ 9
So, not only do certain B vitamins lower homocysteine levels. A number of them play a critical role in the growth and support of nerve cells, and suchlike.
None of this is exactly news. It has been known for centuries that excess alcohol consumption – which blocks Vitamin B1 absorption from the gut – can cause a specific form of dementia called Korsakoff’s dementia. Because of this, people with alcohol problems are often prescribed high dose vitamin B1 (Thiamine).
Which means that it was never a stretch to suggest that giving people B vitamins might be an extremely good thing if you want to prevent, or delay, the progression of Alzheimer’s/brain shrinkage. Either through the benefits on lowering raised homocysteine, or via the critical functions of B vitamins on the structure and function of the brain.
That, anyway, was the underlying science. But does giving B vitamins actually work? Well researchers at Cambridge University certainly believed it was a splendid idea :
‘In an initial, randomized controlled study on elderly subjects with increased dementia risk, we showed that high-dose B-vitamin treatment (folic acid 0.8 mg, vitamin B6 20 mg, vitamin B12 0.5 mg) slowed shrinkage of the whole brain volume over 2 years.’ 10
In a follow-up study, this group of researchers then found that, in people with raised homocysteine levels, who already had signs of dementia, B-vitamins reduced brain destruction and slowed, even halted, the progression of Alzheimer’s. In their own words, from the paper ‘Preventing Alzheimer’s disease-related gray matter atrophy by B-vitamin treatment’:
‘… we showed that high-dose B-vitamin treatment (folic acid 0.8 mg, vitamin B6 20 mg, vitamin B12 0.5 mg) slowed shrinkage of the whole brain volume over 2 years. Here, we go further by demonstrating that B-vitamin treatment reduces, by as much as seven-fold, the cerebral atrophy in those gray matter (GM) regions specifically vulnerable to the AD (Alzheimer’s Disease) process, including the medial temporal lobe. In the placebo group, higher homocysteine levels at baseline are associated with faster GM atrophy, but this deleterious effect is largely prevented by B-vitamin treatment. We additionally show that the beneficial effect of B vitamins is confined to participants with high homocysteine.’ 11
Yes, it was all looking quite good. By the way, this study came out in 2013.
But then we need to factor in the knowledge that B vitamins are very cheap. Very cheap indeed. In addition, they cannot be patented. Which makes it extremely difficult for any pharmaceutical company to make money from them. You can, of course, sell them for a small profit, but pharmaceutical companies need billions to feed the machine. They require unique, patentable, blockbuster drugs. Drugs my precious.
Had any drug shown such a significant effect on brain shrinkage, I am one hundred per cent certain that the finding would have been shouted from the rooftops. We would be looking at a massive blockbuster. Probably the biggest selling drug in the world – ever.
As it was, the research from Cambridge was passed over in virtual silence … I suspect you never heard anything about it. Then, with a certain inevitability, the findings were effectively squashed.
How was this done?
It was done through the power of meta-analysis. A meta-analysis is a fancy term describing an attempt to bring together all the relevant trials that have been done in a therapeutic area. In order to construct a ‘meta’ study, or meta-analysis.
They can be a very useful way to bring together all of the relevant research, where there have been a large number of different studies done. In an attempt to establish the definitive answer to a medical question. Does drug x, or intervention y, actually work. If so, what are the true benefits? Assuming that the trials have all showed subtle, or not so subtle, differences in their effects.
Meta-analyses are often treated as though they are the very pinnacle of medical research. Tablets of stone handed down by Gods. In realty, they need to be treated with a very large pinch of salt, and a healthy dose of scepticism.
This is because meta-analyses often ram together studies with very different populations, using different doses of drugs, or vitamins. Or completely different drugs or vitamins, for different lengths of time.
Just to add to the potential messiness, studies can be included that have completely unrelated outcomes. You end up comparing apples and bananas, in order to decide if pomegranates actually work. In computing it would be called garbage in, garbage out – GIGO.
Moving on, in 2014, the year after the Cambridge study, a whole number of different studies on B-vitamins were brought together in a ‘meta-analysis.’ I use the term meta-analysis very loosely here. It was called: ‘Effects of homocysteine lowering with B vitamins on cognitive aging: meta-analysis of 11 trials with cognitive data on 22,000 individuals.’ 12
Sounds good, so far. In fact, the total number of individuals they looked at was 20,431 – which is a lot nearer to twenty thousand than twenty-two thousand. But, hey ho, what’s sixteen hundred or so people between friends? Having said this deliberate figure inflation is an important indication of researchers trying to ‘big up’ their findings – in my book.
Here’s another thing. A number of the studies had absolutely nothing to do with cognitive function … at all. One of the studies included was HOPE-2. Here is the background to the study.
‘In observational studies, lower homocysteine levels are associated with lower rates of coronary heart disease and stroke. Folic acid and vitamins B6 and B12 lower homocysteine levels. We assessed whether supplementation reduced the risk of major cardiovascular events in patients with vascular disease.’ 13
Yes HOPE-2 was a study on cardiovascular disease. It has absolutely nothing to do with Alzheimer’s, or any other form of dementia. The title of HOPE-2 was ‘Homocysteine Lowering with Folic Acid and B Vitamins in Vascular Disease.’ Cognition, or brain function, was not measured. Yet, it was still included in a meta-analysis of ‘11 trials with cognitive data on 22,000 individuals.’ [20,431 individuals, actually].
Moving on, and this is perhaps more mission critical. In only just over seven thousand of the individuals studied did anyone measure cognitive function at the start of the trial and then again, at the end. Leaving aside such studies as HOPE-2 where it was not measured at all. Which, straight off, means that the vast bulk of this meta-analysis is utterly meaningless.
How can you possibly know what happened to anyone’s cognitive state, if you only measured it once? Did it improve, did it worsen – not the faintest. In two thirds of the individuals included in this meta-analysis we have no idea what happened to cognitive function – at all.
It doesn’t stop here. There were others who felt that this was not meta-analyses finest hour:
‘First and foremost, this meta-analysis excluded trials on mild cognitive impairment (MCI) and Alzheimer’s disease. As a possible consequence, most of the trials included in this meta-analysis either did not see any significant cognitive change (between the start and the end of the trial) in the placebo group or did not look at such change.14
Yes, they specifically excluded people with existing cognitive impairment, or Alzheimer’s, which would be, by far, most important group to study. As they actually have the condition you are interested in.
Which leads to the next obvious problem:
… people included in these trials included in the meta-analysis were healthy and did not show any cognitive decline, whether they received B-vitamin treatment or not. So, B-vitamins could hardly prevent or slow down something not happening in the first place.’ 14
Just to make this point a little clearer, in the minority of studies, where they bothered to measure cognitive function at the start, and also at the end, they found that almost no individuals developed any degree of cognitive impairment – in either group. Not in the treatment group, or the placebo groups. As virtually nothing happened to anyone, nothing could have been proved one way or another.
Attempting to study the progress of dementia, in people who do not have dementia, and who may never get dementia, nor have any signs of cognitive decline … is like doing a blood pressure lowering study on people who do not have a raised blood pressure.
Then, on finding there was no difference in cardiovascular event in either arm of the trial, you proceed to claim that blood pressure lowering does not work. Because there was no difference between those given the drug, and those taking the placebo. Do you think this makes any sense? Answers on a postcard, that should be sent to the Willie Wonka chocolate factory. Care of A.N. Idiot.
Despite begin riddled with fatal flaws, this analysis was greeted as though it was the definitive study. B-vitamins have no effect on cognitive decline, end of. This is what the head of Alzheimer’s Research UK had to say:
‘Although one trial in 2010 showed that for people with high homocysteine, B vitamins had some beneficial effect on the rate of brain shrinkage, this comprehensive review of several trials shows that B vitamins have not been able to slow mental decline as we age, nor are they likely to prevent Alzheimer’s. While the outcome of this new and far-reaching analysis is not what we hoped for, it does underline the need for larger studies to improve certainty around the effects of any treatment.
New and far-reaching analysis. Comprehensive review … ho hum. If I were given the job of marking this meta-analysis, I would hand it back in a rather grumpy fashion. ‘I asked you to look at the benefit of lowering homocysteine, using B-vitamins, in people with cognitive problems, or early-stage Alzheimer’s. Yet, you have not even bothered to look at these groups. In fact, you deliberately excluded them.
In addition, you included trials where the researchers failed to measure mental decline. Added to this, in most of these trials, no-one even had a high homocysteine level to start with, so they cannot – by definition – have had low levels of B-vitamins. So, how could vitamin B supplementation possible have been of any benefit … I am most disappointed. Please try again, and this time READ the brief.’
One of the trials lasted for four months, another for six months. What measurable different in cognitive function can anyone possibly expect to see in those timescales… This was not a flawed meta-analysis. It was simply gibberish.
There was a time when I would have questioned my own sanity in reading a meta-analysis such as this. Surely, I had got it wrong. Researchers would never put together such a steaming pile. If they did, then no-one would publish it. Nowadays I find myself far more in agreement with Drummond Rennie: deputy editor of the Journal of the American Medical Association :
‘There seems to be no study too fragmented, no hypothesis too trivial, no literature citation too biased or too egotistical, no design too warped, no methodology too bungled, no presentation of results too inaccurate, too obscure, and too contradictory, no analysis too self-serving, no argument too circular, no conclusions too trifling or too unjustified, and no grammar and syntax too offensive for a paper to end up in print.’ 15
A famous quote… in certain circles.
As it turns out, this analysis was done by exactly the same people who rule the research world of cholesterol lowering, known as the Cholesterol Treatment Triallists Collaboration (CTT) in Oxford. This paper came under the banner of the ‘B-vitamin treatment triallists collaboration’. Who knew such a group existed? One wonders exactly why they exist? Does the world really require such an organisation?
They sure as hell slammed the door shut on vitamin B/homocysteine research in cognitive function. Which was, some may say, possibly whey they were set up in the first place.
In my opinion, you can either believe the B-vitamin treatment triallists collaboration from Oxford with their meta-analysis. Which some would call complete and utter rubbish. Not me, of course. Personally, I have never seen a more detailed and error free research paper. I can hardly praise it highly enough.
Or, you can believe the Cambridge researchers, who demonstrated a seven-fold reduction in cerebral atrophy with B-vitamins – in those with raised homocysteine levels. The choice is entirely up to you.
1: https://pubmed.ncbi.nlm.nih.gov/29982150/
3: https://pubmed.ncbi.nlm.nih.gov/23172839/
4: https://openheart.bmj.com/content/5/1/e000668
7: https://www.nytimes.com/1997/08/10/magazine/the-fall-and-rise-of-kilmer-mccully.html
8: https://www.nejm.org/doi/full/10.1056/nejmoa011613
9: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930825/
10: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3677457/
11: https://pubmed.ncbi.nlm.nih.gov/23690582/
12: https://academic.oup.com/ajcn/article/100/2/657/4576556
13: https://www.nejm.org/doi/full/10.1056/nejmoa060900
14: https://www.alzheimersresearchuk.org/blog/b-vitamins-and-alzheimers-disease/
15: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3005733/
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