“Manufacturing Doubt”: Sir Cliff Richard weighs in on the Cochrane review.

April 26th, 2008 by Ben Goldacre in bad science, manufacturing doubt, nutritionists, references, statistics | 36 Comments »

Ben Goldacre
The Guardian,
Saturday April 26 2008

And so our ongoing project to learn about evidence through nonsense enters its sixth improbable year. This week, the assembled celebrity community and vitamin pill industry will walk us through the pitfalls of reading through a systematic review and meta-analysis from the Cochrane Collaboration, an international not for profit organisation set up 15 years ago to create transparent, systematic, unbiased reviews of the medical literature on everything from drugs, through surgery, to community interventions. Last week Cochrane produced a comprehensive, gold standard review, looking at 67 trials describing the experiences of 230,000 people, which showed that antioxidant vitamin pills do not reduce deaths, and in fact may increase your chance of dying. [Summary here, full document here, plain language summary on page 2].

In the Health Food Manufacturers Association press release, both Gloria Hunniford and Sir Cliff Richard issued their own definitive refutations. Carole Caplin explained: “It must be obvious to everyone who hasn’t got a vested interest in supplements that this review is absolute rubbish, it contains fundamental flaws.” In a press release issued on behalf of the food supplement industry. Criticising an academic collaboration which does not accept any corporate funding.

So what were these flaws? The entire pill community were worried by the way that trials were selected for inclusion in the group analysis. Dr Rajendra Sharma, ex-head of the Harley Street-ish Hale Clinic – a man who advertises his use of a “bioresonance” machine called the Quantum Xrroid Consciousness Interface to diagnose his patients – explained science to the nation on More4 News. “The writers of this study started with 16,000 studies, and we’re asking the question why did it go down to 68, clearly there’s a bias that we’re not yet quite sure about.”

Let the mystery be revealed. The answer to his question can be found in figure 1 on page 156 of the Cochrane report (which of course he read). Of the 16,111 studies which the Cochrane authors found – by using various search terms in various databases – 12,703 were duplicates, 983 were in children and so not applicable to this review’s predescribed remit, and so on.

Carole Caplin picks up the ball. “With nearly 750 studies to choose from, why did the researchers manage to focus on just 67? That’s less than nine per cent of the total number of clinical trials on antioxidants available.” Well, Carole. Many of those trials were excluded simply because they were not the type of trials being looked at in the study – in accordance with the standard protocol for Cochrane reviews – but 400 trials were excluded because there were no deaths in them. This Cochrane review was a study of deaths, comparing deaths on antioxidant pills to deaths on placebo pills. You need deaths to be reported to put a trial in such an analysis.

These deathless trials were mostly small and brief, representing only 40,000 people in total (page 5, kids). But in any case, as a precaution, the Cochrane authors did a re-analysis of their 230,000 people data, adding in hypothetical fake data, for the 40,000 people, with one death in each of the vitamin and placebo groups: it made no difference. Carole may have skipped that part of the 191 page Cochrane report which she read in full and understood [it's on page 7].

“This isn’t even a new study,” continues Caplin: “it’s simply a re-hash of old work which was widely criticised in 2007 for its inaccuracies.” Interesting point, Carole. This was indeed a reworking of an earlier review published in the journal JAMA, but updated, and in the format required by Cochrane, resulting in a report about 10 times longer than the original journal article. I should hope it did incorporate criticisms from previous work in the same area: this is the whole point of publishing papers, and opening them to informed criticism.

A key question with all research is how to apply it in practice. Are the interventions in the study comparable to the decisions in your real life? “The analysis largely focused on extraordinarily and atypically high doses of antioxidant vitamins,” explained David Adams of the HFMA: “Supplement users would have some trouble trying to replicate this kind of daily intake.”

Well, not that much trouble. I went to Holland and Barrett. In the Cochrane review, the mean dose of betacarotene was 18mg: H&B sell 100 capsules of 15mg betacarotene for £7.49. So practically identical, then. The mean dose of vitamin E was 570 IU: H&B sell 100 capsules of 1000IU – twice that dose – for £19.99. Perhaps David Adams thought nobody would check.

But my favourite insight comes from the actress Jenny Seagrove, and it is a valid one. “I’m not going to be bullied by this dismal research paper – I am 100% confident that the vitamins and mineral supplements I use are safe and effective and I will continue to use them when I choose.” This is the key move. Do you put evidence into practice? Yes: not as an automaton, but at your discretion, taking into account not just the best possible evidence, but also the individuals’ preferences. That is the core of evidence based practice, so munch away, Jenny, and good luck to you. But the publics’ understanding of evidence is far more important than your vitamin pills, so show a little consideration.

· Please send your examples of bad science to bad.science@guardian.co.uk

References:

Mostly in the text above, but because they’re important…

Here is the silly HFMA press release:

www.responsesource.com/releases/rel_display.php?relid=38309&hilite=

Here is the Cochrane review:

mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD007176/pdf_fs.html

Here is the definitive early document on the nature of evidence based practice:

www.bmj.com/cgi/content/full/312/7023/71

And here is a video of Sir Cliff Richard. I think I was just slightly sick in the back of my throat.

[youtube]http://www.youtube.com/watch?v=DrLgdmrFaeU[/youtube]

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Manufacturing Doubt:

The “contriversy” over this Cochrane meta-analysis has been well covered elsewhere, including DrAust, Holfordwatch, Holfordmyths, Quackometer and more.

In many ways what I found most striking were the similarities between the dissembling of the $60bn food supplement pill industry in this case, and the well established strategy of “manufacturing doubt”, first seen in the tobacco lobby’s war with epidemiology over 40 years ago.

The history of this corporate strategy is very well covered in David Michaels’ new book, Doubt is Their Product: How Industry’s Assault on Science Threatens Your Health, on which there is an excellent essay here.

The sabotage of science is now a routine part of American politics. The same corporate strategy of bombarding the courts and regulatory agencies with a barrage of dubious scientific information has been tried on innumerable occasions — and it has nearly always worked, at least for a time. Tobacco. Asbestos. Lead. Vinyl chloride. Chromium. Formaldehyde. Arsenic. Atrazine. Benzene. Beryllium. Mercury. Vioxx. And on and on. In battles over regulating these and many other dangerous substances, money has bought science, and then science — or, more precisely, artificially exaggerated uncertainty about scientific findings — has greatly delayed action to protect public and worker safety. And in many cases, people have died.

Tobacco companies perfected the ruse, which was later copycatted by other polluting or health-endangering industries. One tobacco executive was even dumb enough to write it down in 1969. “Doubt is our product,” reads the infamous memo, “since it is the best means of competing with the ‘body of fact’ that exists in the minds of the general public. It is also the means of establishing a controversy.”


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36 Responses



  1. Nebbish said,

    April 26, 2008 at 1:02 am

    Six years? Congratulations, and celebrations [all together now...]

    But seriously folks, well done, you’re doing good work. Here’s to the next six. And the publication of your book…

  2. CS2TOF said,

    April 26, 2008 at 5:23 am

    Ben,

    Great site – with the right balance of deep thought and levity.

    One comment – you should no longer consider “manufacturing doubt” as just a corporate strategy. It is used equally by citizen’s groups (who, for example, argue that fluoride in the water is totally ‘unsafe’), as it is by many governments (who argue with equal fervor that fluoride is absolutely essential for the nation’s teeth).

    Until we all recognize that “safe” is a relative and not an absolute term (like “tall” – a building can only be taller and/or safer than another), then the real goal, which is enjoying one’s life experiences through judicious decisions based on well-estimated probabilities, remains elusive.

  3. monkeychicken said,

    April 26, 2008 at 8:29 am

    People (the celebrities) straying outside of their sphere of competence is always anger inducing.

    Unfortunately it happens everywhere. I work in the nuclear industry and when it happens there, it can be really scarey.

    Am I the only one who seems to spend their entire life angry?

  4. R N B said,

    April 26, 2008 at 10:52 am

    The criticism was
    “in a press release issued on behalf of the food supplement industry. Criticising an academic collaboration which does not accept any corporate funding.”

    Enough said.

  5. SportsFan said,

    April 26, 2008 at 11:02 am

    Interesting article as always.
    The science here is pretty difficult to dispute. The only only thing I would say is that personally I don’t take vitamins to extend my life. I could get hit by a bus tomorrow and they wouldn’t help me much there. I take vitamins because I have an active lifestyle doing a bit of bodybuilding and a bit of martial arts. Being in my mid forties I feel I need all the help I can get. I’m looking to be fitter now rather than longevity. The received wisdom is that vitamins are the thing.

    Now I’m not completely stupid. I have a reasonably strong suspicion that I am wasting my money, but I don’t want to risk being wrong about that! It is clearly impossible to carry out tests using myself as a subject and have the results mean anything.

    What I would like to see is a review of this nature into whether the use of vitamins is beneficial to the physical performance of active individuals. I’d be more than happy to stop if the received wisdom was shown to be wrong. And I’d save money too.

    And while they’re at it I’d like to see a similar review of protein supplements as used by strength athletes – just to settle a dispute I once had with a doctor.

    Well done Ben for six years of this. You’ve made me re-examine a few beliefs and for that I thank you. Keep it up.

  6. used to be jdc said,

    April 26, 2008 at 11:10 am

    “The analysis largely focused on extraordinarily and atypically high doses of antioxidant vitamins,” explained David Adams of the HFMA: “Supplement users would have some trouble trying to replicate this kind of daily intake.”

    So does David Adams of the HFMA think that it’s only the ‘atypically high doses of antioxidant vitamins’ that are bad?

    Is this the same David Adams that was campaigning to keep higher dose supplements?
    “The director of the U.K.-based Health Food Manufacturers’ Association (HFMA), David Adams, is petitioning British Prime Minister Tony Blair to change legislation banning high-dose vitamin supplements, and CNN reports that Adams is representative of 140 health food firms worldwide who are angry at the European Union ban.” www.naturalnews.com/010086.html

    Also there’s this from a HFMA Position Paper on Beta Carotene:

    In the UK in 1999, the HFMA and
    the Council for Responsible Nutrition (CRN) recommended an upper safe level of 20 mg/day
    for long-term supplementation and a precautionary limit of 20 mg/day for short-term
    supplementation because at this level no adverse effect has been established.

    The HFMA decided that “a dietary supplement containing a modest amount of beta-carotene (5–10 mg/day) may be prudent for health and well-being.” PDF here: www.hfma.co.uk/PositionPaperBetaCarotene.pdf

  7. ACH said,

    April 26, 2008 at 3:47 pm

    Sportsfan – “received wisdom” Received from who? People who are selling you supplements? Dieticians – who are qualified to advise on diet & lifestyle – will tell you that eating a balnced diet gives you sufficient vitamins to be healthy, or at the most, a simple 1 a day multivitamin is sufficient.

  8. emmer said,

    April 26, 2008 at 4:42 pm

    Really excellent article today – thanks!

  9. SportsFan said,

    April 26, 2008 at 6:02 pm

    ACH – Yeah I pretty much agree – hence my dilemma. In recent years I have settled on the one-a-day multvitamin approach as you have suggested. I’m still left wondering though if there is any science recommending any other approach for those active sporty types. Most of the serious nutritional advice we get get appears to be aimed at the average couch potato and I’m yet to be convinced that it applies equally across the board. It is well accepted in weight-training/ bodybuilding circles that you won’t get anywhere without correct diet and I believe that the same applies for most strenuous activity or sport. But then most of the advice comes from magazines sponsored by sports nutrition companies. I’d like science to put some parameters around the area of supplements in sports nuttrition, but then who would pay for it? And with so many real problems to solve why should science bother?

  10. Daibhid C said,

    April 26, 2008 at 8:03 pm

    Ye gods, is *anyone* still listening to Carol Caplin? About *anything*? Did Cheri Blair’s credibility die for nothing?

    Cliff Richard, OTOH, hasn’t aged for thirty years so he must know *something* the rest of us don’t…

  11. Ben Goldacre said,

    April 26, 2008 at 8:35 pm

    Cliff Richard, OTOH, hasn’t aged for thirty years so he must know *something* the rest of us don’t…

    william burroughs looked pretty good until he died well into his eighties. perhaps someone should start advocating a scag diet.

  12. Dave Gould said,

    April 26, 2008 at 10:56 pm

    Yes, can’t find any flaws in the study and thanks for covering it, Ben.

    The only question mark for me is that 81% of studies were sponsored by pharmaceutical companies, notorious for burying studies which don’t support their agenda. What is Big Pharma’s agenda wrt megadose vitamins?

    I was surprised at the extensive media coverage of negative reaction to this study.

    It would be wrong however to assume that Cliff, Carol et al do not receive health benefits. They benefit from the inherent placebo effect – so forgive them for defending that.

  13. Dr Aust said,

    April 26, 2008 at 11:53 pm

    Cliff Richard, I suspect, has many things that often help rich people to look “well preserved”:

    1. Bags of money
    2. Flunkies to do most things for him that ordinary mortals have to do themselves
    3. His own tennis court, gym, swimming pool, chef etc etc
    4. A top-notch cosmetic surgeon who does discreet and subtle work
    5. Botox

    ..anyone got any more suggestions? I was also tempted to add “no children”

  14. don_pedro said,

    April 27, 2008 at 2:47 am

    Dr Aust wrote:

    ..anyone got any more suggestions?

    A portrait of the man, kept locked in the attic, relecting the wear and tear of sustained and depraved debauchery, so that he doesn’t have to.

  15. superburger said,

    April 27, 2008 at 8:26 am

    ben, i hope you thought long and hard before writing negatively about National Treasure Cliff Richard.

    Millions of menopausal women, on hallucinogenic levels of HRT will be after you.

    SportsFan, if you are into running, then you should get a copy of “The Lore of Running” by tim noakes (who is/was a south african medic)

    there’s a good section on supplements (both legal and illegal) in sport – based on hard evidence and the general conclusion is that as long as you are eating a generally healthy diet then most pills and potions are pointless.

    another good argument is that hard, structured training can increase raw speed by >25%, but more importantly endurance (i.e. ability to maintain higher speeds) can increase by 1000s of %. – and the results are easy to measure. No supplement (including illegal ones) can produce these benefits, so for ‘non-elite’ runners good quality training is the number 1 ‘supplement’ but obviously, running 50,60,70 miles a week to improve a marathon time is less attractive than chewing some vitamins.

    In elite athletes (who have presumably trained to their maximum potential) the %ges they are looking to shave are

  16. ACH said,

    April 27, 2008 at 9:56 am

    “BioCare, the vitamin pill company Patrick Holford works for – and received £500,000 from in 2007 – is 30% owned by Elder Pharmaceuticals.”

    Didn’t Holford say (on the infamous Radio 5 admission of more vested interest than Dr Gluud) that he got about a fifth of a drug rep’s salary from Biocare?

    Can someone please direct me to the pharma company that pays its reps £2.5 million. And a reference for a job with them!

  17. Jellytussle said,

    April 27, 2008 at 10:23 am

    But more on that later.
    #
    Dr Aust said,

    April 26, 2008 at 11:53 pm

    Cliff Richard, I suspect, has many things that often help rich people to look “well preserved”:

    1. Bags of money
    2. Flunkies to do most things for him that ordinary mortals have to do themselves
    3. His own tennis court, gym, swimming pool, chef etc etc
    4. A top-notch cosmetic surgeon who does discreet and subtle work
    5. Botox

    ..anyone got any more suggestions? I was also tempted to add “no children”
    #
    don_pedro said,

    April 27, 2008 at 2:47 am

    Dr Aust wrote:

    ..anyone got any more suggestions?

    A portrait of the man, kept locked in the attic, relecting the wear and tear of sustained and depraved debauchery, so that he doesn’t have to.”

    I can confirm that this is true. It is a picture of Keith Richards.

  18. Robert Carnegie said,

    April 27, 2008 at 5:14 pm

    I don’t understand the point that “400 trials were excluded because there were no deaths in them.” I may as well cast the question naively as try to express the precise nature of my concern, so: doesn’t picking only trials in which people die create a bias in which the therapy on trial appears to be associated with deaths?

    I suppose also that it could be conceivably that antioxidants improve the quality of life whilst not making it less likely to end during a trial period, or even more likely. For instance if the pill cures your disease but itself may kill you. Perhaps that is covered by combining trials of healthy people and trials specifically of the sick.

    Finally, what does “Harley Street-ish” mean, is it like off-Broadway, and where in the world do you find people to be impressed by a “Quantum Xrroid Consciousness Interface” instead of running, or hobbling, a metric mile upon hearing of the thing?

  19. Dr Aust said,

    April 27, 2008 at 8:06 pm

    Robert, re the trials with no deaths being excluded, we had a discn about this over at Holfordwatch here.

    The basic point is that they mean that they excluded trials where there were no deaths in either the control or the supplement patient groups. If you are measuring and comparing death rate you need enough deaths to measure.

  20. Dave Gould said,

    April 28, 2008 at 12:07 am

    The study authors believe that a death in a study does not bias the study towards or against vitamins.

    One could propose the theory that vitamins are bad for most but good for for everyone else.

    Another theory would be that people who correctly believed they were going to die both knew they weren’t taking placebo and were much less likely to drop out of the studies. There was a small difference between healthy and disease-based studies that might show this.

    The other notable correlation found is that those studies which the authors could verify as being more scientific showed an even worse result for vitamins.

    Furthermore, the authors included 4 studies without placebo controls and still couldn’t find a benefit.

    The increased mortality rate is so small that it’s not worth paying attention to.

    What hard to dispute here is that if megadose vitamins make the general population live longer, it’s so tiny as for that effect to be discounted.

    Mind you, the same can be said for nearly all medications.

  21. Robert Carnegie said,

    April 28, 2008 at 1:37 am

    Yes… are we saying that zero isn’t a measurement? I’ll look at HolfordWatch. …On second thoughts, that’s very wordy, I see. Perhaps I’ll abide in ignorance.

    If there are studies that didn’t keep count of people who did die, that’s… surprising.

  22. Moganero said,

    April 28, 2008 at 10:18 am

    A bit off topic, but I noticed that Holland and Barrett in Hanley, Stoke-on-Trent still has stickers on their shelves showing _Dr_ Gillian McKeith recommended some of their products. They didn’t seem to be in the slightest bit bothered when I mentioned it to them, but then maybe it helps them sell more.

  23. CDavis said,

    April 28, 2008 at 1:32 pm

    You and Cochrane et al neglected to mention it, but no doubt you’ll make an exception for raw glucose – 20,000 Lucozade drinkers can’t be wrong, can they?

    Sporty types need ‘energy’ – so *they* drink it, apparently. Therefore millions of couch-potatoes who wish they could look like sporty types drink it too, by the gigacalorie. Stands to reason.

    CD

  24. used to be jdc said,

    April 28, 2008 at 4:37 pm

    Heh. The ANH has a shockingly bad press release on the Bjelakovic study which ends with an accusation framed as a question (hm, weaselly) – PDF.

    The insinuation is that the Cochrane collaboration is ‘under the influence of drug companies’ – which is really quite amusing given that one of the writers of the press release defending supplements was (at least until recently) employed by a firm selling food supplements (Ultralife). The other writer was working at Nutrition Associates Ltd – who offer medical advice and treatments based on nutrition and allergy principles, which can mean recommending tests using, e.g., Great Smokies Diagnostic Laboratory and YorkTest.

  25. Dr Aust said,

    April 28, 2008 at 5:52 pm

    The authors actually explain how they INCLUDED several studies in which death rate was reported AND was zero in ONE group (which could be either controls, or the vitamin-takers, as no upfront assumptions were made). That is, these studies WERE included, contrary to what all the vitamin industry PR flacks and celeb-idiots have been wheeled out to try to tell you.

    Zero in BOTH groups gives you NO information from which you can estimate the DIFFERENCE in mortality rate plus/minus supplements in the “populations” from which the study group are derived. All you can say is “overall death rate in the underlying populations from which these groups were derived probably can’t be greater than x%, as if it were bigger than this we would expect to have seen some deaths in a study this size”.

    This is the other side of what the stats people call “power calculations”. The studies w no death rates in either group are,as the stats lot say, “underpowered” for telling you anything useful about death rates, though they may have recorded other “outcome measures”.

  26. evidencebasedeating said,

    April 29, 2008 at 11:04 pm

    hmmmmmm

    plant mmmmmmmmmmmmmmm

    mmmmmmmmmm

  27. Craig said,

    May 1, 2008 at 5:44 am

    The repeated conclusions of reputable vitamin supplement studies appear to be along the lines of “so long as you’re eating a balanced diet, don’t bother…”

    However: I don’t eat a balanced diet.

    Partly that’s because I do a lot of bushwalking and long-haul motorcycle touring (where I’m surviving on either instant noodles or dodgy roadhouse food for extended periods), but it’s also partly ‘cos I’m a geeky science student who drinks too much, smokes too much and routinely forgets to eat.

    So: given that I don’t have a nutritionally great diet, and that’s unlikely to change anytime soon, is a daily multivitamin worth the money? Or is it still going to be just providing value-added urine?

  28. used to be jdc said,

    May 1, 2008 at 12:30 pm

    Maybe ask a dietitian Craig? If you are talking about taking supplements as ‘insurance’, Catherine Collins made a comment about vit supplements here: holfordwatch.info/about/#comment-2964 – but I don’t imagine for a moment that a vitamin pill is going to make up for drinking too much, smoking too much and routinely forgetting to eat.
    BDA food facts here: www.bda.uk.com/Downloads/November04foodfacts.pdf is written by Catherine Collins.

  29. Robert Carnegie said,

    May 2, 2008 at 2:42 am

    No deaths means quite a high count of people who didn’t die.
    How does this pooling work, though? Do well-regulated studies have equal size groups, or different groups? Do you Cochrane them by just adding eveyone together into bigger groups?

    Can you program the Dymo label printer currently advertised to print thousands of labels saying “Not a real doctor”, to smuggle into your local shop selling “Dr.” Gillian McKeith products? Bonus if you also make them say “reduced”, because arguably she is. And I think the sell by date may apply.

  30. kiwitranslations said,

    May 4, 2008 at 9:46 am

    I would like to know what Ben (and everyone else) thinks about the methods and conclusions of Ray Kurzweil and Terry Grossman. They advocate aggressive supplementation, which makes them suspect in the light of this conversation, but they make a big deal about basing it all on hard science, referencing medical studies for every point they make. The former of the two is highly accomplished in his own specialty (not medicine) and the latter is a medical professional. But how good is their science really? Is it bad science?

    One other point, saying “just eat a well-balanced diet” really just begs the question: what is “well-balanced?” At the end of the day, whether it comes through conventional food or in the form of pills we still face the question of what quantities of various nutrients result in optimal health (if we are interested in achieving that).

  31. Ben S. said,

    September 26, 2013 at 11:36 pm

    First of all, for a

    To refute this, I would like to note the following:

    A re-examination of an early version of this Cochrane review noted:

    “A recent meta-analysis of selected randomized clinical trials (RCTs), in which population groups of differing ages and health status were supplemented with various doses of b-carotene, vitamin A, and/or vitamin E, found that these interventions increased all-cause mortality. However, this meta-analysis did not consider the rationale of the constituent RCTs for antioxidant supplementation, none of which included mortality as a primary outcome. As the rationale for these trials was to test the hypothesis of a potential benefit of antioxidant supplementation, an alternative approach to a systematic evaluation of these RCTs would be to evaluate this outcome relative to the putative risk of greater total mortality. Thus, we examined these data based on the primary outcome of the 66 RCTs included in the meta-analysis via a decision analysis to identify whether the results provided a positive (i.e., benefit), null or negative (i.e., harm) outcome. Our evaluation indicated that of these RCTs, 24 had a positive outcome, 39 had a null outcome, and 3 had a negative outcome. We further categorized these interventions as primary (risk reduction in healthy populations) or secondary (slowing pathogenesis or preventing recurrent events and/or cause-specific mortality) prevention or therapeutic (treatment to improve quality of life, limit complications, and/or provide rehabilitation) studies, and determined positive outcomes in 8 of 20 primary prevention studies, 10 of 34 secondary prevention studies, and 6 out of 16 therapeutic studies. Seven of the eight RCTs with a positive outcome in primary prevention included participants in a population where malnutrition is frequently described. These results suggest that analyses of potential risks from antioxidant supplementation should be placed in the context of a benefit/risk ratio.”: www.mdpi.com/2072-6643/2/9/929

    Also, a 2011 meta-analysis controverted this, noted that supplementation with vitamin E appears to have no effect on all-cause mortality at doses up to 5,500 IU/d: www.ncbi.nlm.nih.gov/pubmed/21235492

    AK5 made relevant commentary. I would like to add to that the fact that synthetic vs. natural vitamin E is one case in which there are genuine differences in mechanism of action and toxicity, with the synthetic being more dangerous: www.greenmedinfo.com/toxic-ingredient/dl-alpha-tocopherol-acetate

    This does not apply to vitamin C, which is perfectly fine as ascorbic acid. Vitamin C is also extremely safe at extremely high doses:

    Vitamin A,D, and K2 are synergistic, and vitamins A or D alone will exhibit a toxicity that, when taken together, especially with the other, they do not. See, for partial proof of this, the following: www.ncbi.nlm.nih.gov/pubmed/17145139 – see, for full proof of this, the relevant discussion in the book “The Perfect Health Diet” by the Jaminets, but for more on vitamin A – to prove this fact, see this: www.westonaprice.org/fat-soluble-activators/vitamin-a-on-trial, for more on vitamin D, see this: www.westonaprice.org/blogs/2010/12/16/is-vitamin-d-safe-still-depends-on-vitamins-a-and-k-testimonials-and-a-human-study/, and for vitamin K2, which ties everything together, see this: www.westonaprice.org/fat-soluble-activators/x-factor-is-vitamin-k2 – enormous benefit is gained from animal fat based diets that are very high in all three in conjunction, this was proven in Weston Price’s book “Nutrition and Physical Degeneration” – some responses to misinterpretations about that work is here: www.westonaprice.org/basics/the-right-price, www.westonaprice.org/traditional-diets/nasty-brutish-short

    I also have skepticism about morbidity claims for 2 justifiable reasons:

    1) In a 2008 review Does pharmaceutical advertising affect journal publication about dietary supplements?, Kemper, et al., report that “Journals with the most pharmads published no clinical trials or cohort studies about DS. The percentage of major articles concluding that DS were unsafe was 4% in journals with fewest and 67% among those with the most pharmads (P = 0.02). The percentage of articles concluding that DS were ineffective was 50% higher among journals with more than among those with fewer pharmads (P = 0.4).”: www.biomedcentral.com/1472-6882/8/11

    2) Morbidity claims are also inconsistent with real world data. Data on fatalities comes from the American Association of Poison Control Centers. In determining cause of death, AAPCC uses a 6-point scale called Relative Contribution to Fatality (RCF). A rating of 1 means “Undoubtedly Responsible”; 2 means “Probably Responsible”; 3 means “Contributory”; 4 means “Probably Not Responsible”; 5 means “Clearly not responsible (and Not Contributory)”; 6 means “Unknown – In the opinion of the Case Review Team the Clinical Case Evidence was insufficient to impute or refute a causative relationship for the SUBSTANCES in this death.” (see p. 832 0f the 2006 document, below, to verify my citations).

    The American Association of Poison Control Centers (AAPCC) attributes annual deaths to vitamins as (for all of these, refer to the page numbers of the document, not the pdf):

    2010: zero – see p. 139: aapcc.s3.amazonaws.com/pdfs/annual_reports/2010_NPDS_Annual_Report.pdf
    2009: zero – see p. 1148: aapcc.s3.amazonaws.com/pdfs/annual_reports/NPDS_Annual_Report_2009_1.pdf
    2008: zero – see p. 1053: aapcc.s3.amazonaws.com/pdfs/annual_reports/NPDS_Annual_Report_2008_1.pdf
    2007: zero – see p. 1028: aapcc.s3.amazonaws.com/pdfs/annual_reports/2007annualreport.pdf
    2006: one – see p. 890 – for this, RCF is 4 – probably not responsible – see p. 871 – and in this, the vitamin is of “unknown” category (again see p. 890): aapcc.s3.amazonaws.com/pdfs/annual_reports/2006_Annual_Report_Final.pdf
    2005: one – see p. 915 – RCF is not given – again, of “unknown” category: aapcc.s3.amazonaws.com/pdfs/annual_reports/Clin-Tox_AAPCC_2005_Annual_Report.pdf
    2004: three – see p. 653 – RCF is not given – one from a multi-vitamin with iron, one from vitamin D, and one from Viamin E – but since RCF is not given, we cannot make any meaningful statements about this: aapcc.s3.amazonaws.com/pdfs/annual_reports/AJEM_-_AAPCC_Annual_Report_2004.pdf
    2003: four – see p . 392 – RCF is not given – this is of a multi-vitamin with iron, vitamin B6, vitamin c, and a multi-vitamin with iron – but since RCF is not given, we cannot make any meaningful statements about this: aapcc.s3.amazonaws.com/pdfs/annual_reports/AJEM_-_AAPCC_Annual_Report_2003.pdf
    2002: one – see p. 410 – RCF is not given – vitamin E – but since RCF is not given, we cannot make any meaningful statements about this:aapcc.s3.amazonaws.com/pdfs/annual_reports/AJEM_-_AAPCC_Annual_Report_2002.pdf
    2001: zero – see p. 443: aapcc.s3.amazonaws.com/pdfs/annual_reports/NPDS_Annual_Report_2001.pdf
    2000: zero – see p. 387: aapcc.s3.amazonaws.com/pdfs/annual_reports/NPDS_Annual_Report_2000.pdf
    1999: two – see p. 566 – from multivitamin with iron – RCF is not given – again, RCF is not given, so we cannot make any meaningful statements about this: aapcc.s3.amazonaws.com/pdfs/annual_reports/AJEM_-_AAPCC_Annual_Report_1999.pdf

  32. Ben S. said,

    September 26, 2013 at 11:37 pm

    For the original item, I wanted to provide this database showing the medical benefit of above RDA supplementation: www.lef.org/abstracts/index.htm

  33. Ben S. said,

    September 27, 2013 at 12:03 am

    For vitamin C safety at very high doses, I wanted to provide the following study: www.ncbi.nlm.nih.gov/pubmed/20628650

    An author of that study also made another study “Vitamin C Pharmacokinetics: Implications for Oral and Intravenous Use”, which looked at reevaluating results for vitamin c and cancer (which, evidence has shown is at best an adjunctive optimization of traditional treatment: www.ncbi.nlm.nih.gov/pubmed/22021693, www.ncbi.nlm.nih.gov/pubmed/6811475 and is in some cases synergistic: www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0029794 (for this, see discussion and figure 3 of the trial: www.plosone.org/article/info:doi/10.1371/journal.pone.0029794.g003/originalimage, as it is easy to have a misreading of it), and there is this: link.springer.com/article/10.1007/s00280-013-2070-8, and this trial shows high synergy in the animal model: www.ncbi.nlm.nih.gov/pubmed/21402145) though I’m much more interested in vitamin c for infectious diseases and toxins. The study is here: annals.org/article.aspx?articleid=717329

    Figure 2 of the study has major importance for vitamin c in treating the common cold. Its implications are self evident. It shows why some experiments with vitamin C have succeeded and others haven’t. This shows why intravenous administration may be necessary for infectious diseases, you get results like that reported in the initially linked item- it also shows why, for oral dosing, administration of frequent large oral doses is necessary: annals.org/DownloadImage.aspx?image=%2Fdata%2FJournals%2FAIM%2F20062%2F10FF2.jpeg&sec=24171406&ar=717329&imagename

    The fact that for oral administration, large, frequent doses are necessary for a significant effect has been worked out by researchers in the field – in the development of the dynamic flow model: www.medicalnewstoday.com/releases/10022.php

    A conclusion to a review of vitamin C pharmacokinetics concluded (this is in the article, not the abstract): “once or twice daily mega-dose supplementation of ascorbate will not load tissues, such as red blood cells, or increase the body pool substantially; and therefore, would not be expected to show more than a minimal biological effect, when compared with the dynamic flow model.”: www.ncbi.nlm.nih.gov/pubmed/18450228

    It explains why you get such discrepancies in the literature. And it resolves the vitamin C and the common cold controversy:

    Traditional studies show prevention, not treatment, because of failing to take into consideration the method of dosage advocated by the original advocates (like Irwin Stone, who promoted vitamin C to Linus Pauling, and who recommended 1-2 g/hour at the onset of a cold). A randomized, double-blind (but not placebo-controlled) study reported that those who took 500 mg/day of supplemental vitamin C had a 66% lower risk for contracting three or more colds in a five-year period compared to those who took 50 mg/day of supplemental vitamin C. It did not find any significant differences in the two groups when analyzing data regarding cold severity or duration, but these were small doses: www.ncbi.nlm.nih.gov/pubmed/16118650

    A Cochrane Review of Vitamin C supplementation for colds found that vitamin C supplementation did not shorten the duration of colds in seven placebo-controlled trials at doses ranging from 1-4 grams/day. Additionally, the same authors completed a meta-analysis of the 15 trials that assessed the effect of vitamin C on cold severity; no consistent evidence that vitamin C was beneficial in ameliorating cold symptoms was found in this analysis. The overall conclusion of this meta-analysis was that vitamin C is ineffective as a prophylactic against the common cold, but individuals under stress, such as those exposed to strenuous physical exercise or cold weather, may experience some therapeutic benefit. It did note, however, that one large trial reported equivocal benefit from an 8 gram therapeutic dose at onset of symptoms: www.ncbi.nlm.nih.gov/pubmed/15495002

    This review has been criticized, with one critic noting that “There is widespread confusion about nutritional and pharmacological levels of supplementation. Linus Pauling, typically, described nutritional gram-level doses able to provide a degree of disease prevention. By contrast, pharmacological doses used for treatment are, at minimum, an order of magnitude larger and involve frequent doses. … Douglas and Hemilä have only confirmed that 60 years of vitamin C research has largely been wasted because of confusion between nutritional and pharmacological intakes, and because of a misunderstanding of the pharmacokinetics.”: www.ncbi.nlm.nih.gov/pubmed/16173838

    Another criticism noted that “In the Cochrane review by Douglas et al. [1], which is referenced in the Best Practice article by Douglas and Hemilä [2], there was no mention of the revealing paper published last year by Padayatty et al. [3], which shows that three-times greater blood concentration can be achieved with an oral dose of vitamin C than previously thought possible. Since viruses increase the demand for ascorbic acid, the oral doses used in the reviewed studies appear trivial, and would not be expected to produce any positive effect. Compare human oral dose studies to what animals synthesize throughout the day. It is obvious that a single dose of a water-soluble vitamin, regardless of the number of milligrams consumed, will not elevate blood plasma levels enough to produce a preventive or therapeutic effect.”: www.ncbi.nlm.nih.gov/pmc/articles/PMC1236802/

    (The pharmacokinetic study that had been mentioned was the one previously given in this message from which the figure was derived).

    Harri Hemilä (author of the review) stated in response that “The responses to our Best Practice article [1] by Hickey and Roberts [2], and by Sardi [3], make the same point, namely, that a recent pharmacokinetic study reported that frequent oral intakes of vitamin C would be necessary to elevate plasma ascorbic acid levels to the point where they believe it would have a pharmacological impact. Both authors suggest that the conclusions of our Cochrane review [4] are flawed because all of the placebo-controlled trials that have been carried out so far have used, for both prophylaxis and therapy, one to three doses per day of vitamin C, ranging from 200 mg daily to as much as 8 g in a single daily dose.” [...] the claim that these two letters make has not been reported in properly conducted randomized controlled trials of either therapy or prophylaxis. We look forward to incorporating such trials, when they have been carried out, in future versions of the Cochrane review. Meanwhile, we stand firmly by the conclusions reported in our article.”: www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.0020309

    However, there are good studies showing an effect from large frequent doses that should be the basis of future randomized controlled trials:

    In “How to Live Longer and Feel Better” (Oregon State University Press, 2006), Linus Pauling notes a study that matched all the criteria that the above critics of the Cochrane Review called for, and is consistent with the results of the aforementioned pharmacokinetic study on Vitamin C [along with an analysis of studies supposedly debunking the therapeutic efficacy of Vitamin C, showing that they did show a notable percentage decrease of symptoms – it is also interesting that the 1975 study from Karlowski that has long served to supposedly “debunk” the idea that vitamin C can treat the cold was later analyzed by Hemila, and Hemila found that “Karlowski et al, found a 17% decrease in the duration of cold episodes in the group administered vitamin C (6 g/day); however, they suggested that the decrease was entirely due to the placebo effect. In this article it will be shown that the placebo effect is not a valid explanation for the results of the Karlowski study, as it is inconsistent with their results. This is an important conclusion for two reasons. First, the placebo explanation becomes even more unreasonable as regards the reported benefits found in several other studies with valid placebo tablets. Second, as the results from the Karlowski study are not due to the placebo effect, their results can be used to assess the quantitative effects of vitamin C supplementation.”: www.ncbi.nlm.nih.gov/pubmed/8826986

    Hemila also noted, noted, regarding Stephen Barrett’s dismissals of the role of vitamin C in treating the cold: www.mv.helsinki.fi/home/hemila/experts/#mozTocId556924

    “Barrett’s presentation of facts related to the findings from studies on vitamin C and the common cold have been markedly biased. In a comment on Barrett’s paper (1995) claiming there is no evidence that vitamin C might affect colds, Hemilä (1995b) pointed out that “Anderson et al. (1972) found that vitamin C supplementation (1-4 g/ day) decreased the ‘numbers of days confined to house’ per subject by 48% in subjects with a low dietary intake of fruit juices [see Hemilä 2006 Table 13, p 35]. Barrett’s claim that at best there is only a slight reduction in symptoms appears grossly misleading considering the published results.” Stephen Barrett replied to this that “Anderson’s first study found … a 30% difference.” In a subsequent letter Edgar Villchur (1995) pointed out that “Barrett’s reply in the same issue challenges Hemilä’s reporting accuracy, but Hemilä is correct … Barrett, however, doesn’t say he is citing a different part of the Anderson data, and thus makes it seem that Hemilä has either misread or misrepresented Anderson.” In a reply to this accusation, Stephen Barrett (1995) conceded that “Villchur is correct that Hemilä and I referred to different figures.””

    And aside from that, Hemila also debunked a previous dismissive review that erroneously shaped public opinion to the effect that vitamin C has no effect on the common cold: www.mv.helsinki.fi/home/hemila/H/HH_1995.pdf

    But what follows is evidence that had been overlooked in even these laudable efforts:]

    In the book (p. 125), Pauling states, “The best study of the therapeutic effect of Vitamin C was carried out by Asfora (1977) [the study is "Vitamin C in High Doses in the Treatment of the Common Cold", in Re-evaluation of Vitamin C, eds. A. Hanck and G Ritzel. Hans Huber, Bern, pp.219-234], who gave 30 g or a placebo to 133 subjects (medical students, physicians, or clinic patients in Pernambuco) who had reported a developing cold. The Vitamin C was given as effervescent 1000-mg tablets, with instructions that six should be taken each day (two at a time, three times a day) for five days; the placebo consisted of similar effervescent tablets. Some patients began on the first day of the cold, others on the second, and others on the third, as shown on the table below [table provided in text].

    The number of subjects for whom the treatment may be said to have failed completely, in that they developed secondary bacterial infections and were ill for an average of 15 days, was 13 percent for the first day vitamin-C subjects, 20 percent for the second-day subjects, and 41 percent for the third day subjects (also 39 percent for the placebo group). For the remaining subjects in each group, whose colds were without complication, the average number of days of illness was 1.82, 2.71, and 5.10 for the first-, second-, and third-day subjects. We see that 6 g of vitamin C per day, starting on the first or second day of the cold, stopped it for most of the subjects in this investigation.”

    The study closest to the demanded pharmacokinetic requirements, much more recent, showed an 85% reduction in symptoms compared to the control group. In this study, “Those in the control population reporting symptoms were treated with pain relievers and decongestants, whereas those in the test population reporting symptoms were treated with hourly doses of 1000 mg of Vitamin C for the first 6 hours and then 3 times daily thereafter. Those not reporting symptoms in the test group were also administered 1000-mg doses 3 times daily.”: www.ncbi.nlm.nih.gov/pubmed?orig_db=PubMed&term=The+effectiveness+of+vitamin+C+in+preventing+and+relieving+the+symptoms+of+virus-induced+respiratory+infection&cmd=search&cmd_current

    Hemila has noted some efficacy for zinc in the treatment of the cold: www.ncbi.nlm.nih.gov/pmc/articles/PMC3136969

    There was a recent review of 2 randomized placebo-controlled trials treating the common cold with vitamin c and zinc combined that showed efficacy: www.ncbi.nlm.nih.gov/m/pubmed/22429343/

    So randomized controlled trials of zinc in combination with the high frequent doses of vitamin c protocol that showed 85% success for treatment of the cold might solve this problem that has been plaguing researchers for quite some time, and provide a nutritional cure (or at least powerful treatment) for the cold. Intravenous administration of vitamin C might be even more (perhaps drastically more) effective.

    For infectious diseases, I’m sure you’ve heard of the New Zealand 60 min story concerning a man from New Zealand who was at death’s door from severe swine flu, but his family had the doctors intervene with iv vitamin c administration. He recovered completely. This was the isolated causative factor that did it, you can see the story on this here: vimeo.com/23598532

    Other evidence for the efficacy of intravenous administration for infectious diseases and toxins (if there is penetration into the mainstream for this therapy, this is where it will be), is here: injectablevitaminc.com/download.html

    – Ben Steigmann

  34. Ben S. said,

    September 27, 2013 at 12:39 am

    There is this review, “Vitamin C: A Concentration-Function Approach Yields Pharmacology and Therapeutic Discoveries” – it clarifies some things related to this: advances.nutrition.org/content/2/2/78.full

    A lot of the text focuses on cancer because of some enthusiasm over positive case series: www.ncbi.nlm.nih.gov/pmc/articles/PMC1405876/, in vitro studies: www.ncbi.nlm.nih.gov/pubmed/16157892?dopt=Abstract,

    But what I have presented above is the best evidence for vitamin C and cancer and it shows that it is adjunctive, but in no way a replacement for traditional therapies (by the way, I do not have it on me now, so I can’t give you the exact quote, but from what I remember, Pauling argued that vitamin C be used in conjunction with traditional treatment explicitly at the end of the relevant chapter of “How to Live Longer and Feel Better”, In “Vitamin C and Cancer” (1993), p. 130, he stated explicitly, “Vitamin C is not a miraculous cure for cancer, but it [I would add, in intravenous administration] goes a long way toward the therapeutic goal outlined in chapter 4.” So he DID NOT say that Vitamin C cured cancer, as his critics like to mistakenly say about him. He went on to explain that this goal was increase in survival times, and improvement in quality of life. One very recent multicenter study that I gave you showed improvement in quality of life: www.ncbi.nlm.nih.gov/pubmed/22021693 And that text of Pauling’s was 1979 text, I think, as much of the rest of it is 1979 text, aside from the preface, which is 1993 text. Shortly after 1979, both of those claims for vitamin C were independently corroborated: www.ncbi.nlm.nih.gov/pubmed/6811475)

    But we know all this now, but from what I have given above, the real evidence for vitamin c lies, again, with infectious diseases and toxins. The authors of “Vitamin C: A Concentration-Function Approach Yields Pharmacology and Therapeutic Discoveries” also suggested a role for infections in a specific case, but I feel that the surface is barely beginning to be brushed.

  35. Ben S. said,

    September 27, 2013 at 12:52 am

    ^ I meant to also include animal studies in that statement “because of some enthusiasm ” – here is the study: www.ncbi.nlm.nih.gov/pmc/articles/PMC2516281/ , and some insight into pharmacology is given here: www.sciencedirect.com/science/article/pii/S0304419X12000509

    However, as I will reiterate again, I feel that the importance of this therapy lies in its use with infectious diseases and toxins. Here is a very relevant book, portions of which are on Google preview, called “Vitamin C, Infectious Diseases, And Toxins”: books.google.com/books?id=cvNZ_LKcsXMC&printsec=frontcover#v=onepage&q&f=false

    The book has since been updated under the title “Curing the Incurable”. That might seem like an over the top title, but the New Zealand 60 minutes story that I gave above, as well as the information I gave directly below it, supports the use of such words. That book is not peer-reviewed, and it is not from a mainstream publisher. I hope that you will not use logical fallacies when approaching it because of this (poisoning the well, appeal to popularity, appeal to authority (the authority of mainstream publishers), or whatever else) though, as it is a compendium of independently verifiable esoteric information that many might otherwise overlook, and therein lies its value. For instance, I found in that book the controlled study showing 85% reduction in cold symptoms in people using a method of administration consistent with the above given pharmacokinetic observations.

  36. Ben S. said,

    September 27, 2013 at 1:08 am

    When I said “Initially linked item” above, I meant to comment on this study, “The Treatment of Poliomyelitis and Other Virus Diseases with Vitamin C” (Southern Medicine & Surgery, Volume 111, Number 7, July, 1949, pp. 209-214): web.archive.org/web/20120211074211/http://www.seanet.com/~alexs/ascorbate/194x/klenner-fr-southern_med_surg-1949-v111-n7-p209.htm

    The commentary in it is relevant:
    “In the poliomyelitis epidemic in North Carolina in 1948, 60 cases of this disease came under our care. These patients presented all or almost all of these signs and symptoms: Fever of 101 to 104.6�, headache, pain at the back of the eyes, conjunctivitis, scarlet throat; pain between the shoulders, the back of the neck, one or more extremity, the lumbar back; nausea, vomiting and constipation. In 15 of these cases the diagnosis was confirmed by lumbar puncture; the cell count ranging from 33 to 125. Eight had been in contact with a proven case; two of this group received spinal taps. Examination of the spinal fluid was not carried out in others for the reasons: (1) Flexner and Amoss had warned that “simple lumbar puncture attended with even very slight hemorrhage opens the way for the passage of the virus from the blood into the central nervous system and thus promotes infection.” (2) A patient presenting all or almost all of the above signs and symptoms during an epidemic of poliomyelitis must be considered infected with this virus. (3) Routine lumbar puncture would have made it obligatory to report each case as diagnosed to the health authorities. This would have deprived myself of valuable clinical material and the patients of most valuable therapy, since they would have been removed to a receiving center in a nearby town.

    The treatment employed was vitamin C in massive doses. It was given like any other antibiotic every two to four hours. The initial dose was 1000 to 2000 mg., depending on age. Children up to four years received the injections intramuscularly. Since laboratory facilitates for whole blood and urine determinations of the concentration of vitamin C were not available, the temperature curve was adopted as the guide for additional medication. The rectal temperature was recorded every two hours. No temperature response after the second hour was taken to indicate the second 1000 or 2000 mg. If there was a drop in fever after two hours, two more hours was allowed before the second dose. This schedule was followed for 24 hours. After this time the fever was consistently down, so the drug was given 1000 to 2000 mg. every six hours for the next 48 hours. All patients were clinically well after 72 hours. After three patients had a relapse the drug was continued for at least 48 hours longer — 1000 to 2000 mg. every eight to 12 hours. Where spinal taps were performed, it was the rule to find a reversion of the fluid to normal after the second day of treatment.

    For patients treated in the home the dose schedule was 2000 mg. by needle every six hours, supplemented by 1000 to 2000 mg. every two hours by mouth. The tablet was crushed and dissolved in fruit juice. All of the natural “C” in fruit juice is taken up by the body; this made us expect catalytic action from this medium. Rutin, 20 mg., was used with vitamin C by mouth in a few cases, instead of the fruit juice. Hawley and others have shown that vitamin C taken by mouth will show its peak of excretion in the urine in from four to six hours. Intravenous administration produces this peak in from one to three hours. By this route, however, the concentration in the blood is raised so suddenly that a transitory overflow into the urine results before the tissues are saturated. Some authorities suggest that the subcutaneous method is the most conservative in terms of vitamin C loss, but this factor is overwhelmingly neutralized by the factor of pain inflicted.

    Two patients in this series of 60 regurgitated fluid through the nose. This was interpreted as representing the dangerous bulbar type. For a patient in this category postural drainage, oxygen administration, in some cases tracheotomy, needs to be instituted, until the vitamin C has had sufficient time to work — in our experience 36 hours. Failure to recognize this factor might sacrifice the chance of recovery. With these precautions taken, every patient of this series recovered uneventfully within three to five days.”