Antioxidant supplements are bad for you

[Bjonnh]

http://pipeline.corante.com/archives/2014/02/05/the_evidence_piles_up_antioxidant_supplements_are_bad_for_you.php

I was thinking it would be of some interest for some Kurz-kind of
people over there.

[Mega [Andreas Stuermer]]

Hehe... There once was a TV quote "what if my body runs out of oxidants?!"

It seems he wasn't that wrong at all :P

[LawrenceHI]

I'd appreciate some clarification on this one. Why is Monsanto breeding broccoli that is higher in antioxidants then? Maybe the biotech is planning the inevitable ban on GM crops so they can poison us with high anti oxidant organic vegies! :O 

Why does it always seem like this is a either/or issue for a lot of people? Well, because it is easier to think in dualities than remain open and critically think keeping in mind that the current system is thoroughly corrupt.

[Nathan McCorkle]

It's hard to believe any of this as absolute truth, because nutrition
has a very wide scope, and depends on your genetics and epigenetics.
So what's true for one person isn't for another living in similar
conditions.

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[Nathan McCorkle]

On Sat, Feb 8, 2014 at 3:26 PM, Nathan McCorkle <nmz...@gmail.com> wrote:
> It's hard to believe any of this as absolute truth, because nutrition
> has a very wide scope, and depends on your genetics and epigenetics.
> So what's true for one person isn't for another living in similar
> conditions.

*isn't always*

[Patrik D'haeseleer]

Yeah well - ALL overgeneralizations are wrong anyway.

Patrik

[David Murphy]

>It's hard to believe any of this as absolute truth, because nutrition
>has a very wide scope, and depends on your genetics and epigenetics.
>So what's true for one person isn't for another living in similar
>conditions.

Sure and arsenic might be super good for just you and nobody else.

It's been known for a long time that antioxidants weren't good for your health (the health food market and popular culture was about 20 years behind the times on that one). Trials to test if antioxidants were good for your health had to be stopped because so many additional people were dying.

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[Cathal Garvey]

Arsenic is an important micronutrient.

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[Bjonnh]

On Sun, Feb 09, 2014 at 04:05:56PM +0000, David Murphy wrote:
> Trials to test if antioxidants were good for
> your health had to be stopped because so many additional people were dying.

Really ? Do you have sources about that ?

[Cathal Garvey]

NB all: I rabbited this commonly-said-factoid, only to go digging and
find no evidence to support it. So, David's right about As. Arsenic bad. ;)

That said, I still hold that the jury is still out on antioxidants. By
their nature, they straddle the redox spectrum, and under some
circumstances can make things *more* oxidative. They may also, if taken
in purified form, perhaps do funny things in the highly acidic stomach
environment; recall that natural dietary antioxidants are often
encapsulated in undigested plant matter at this phase.

Because of their variable behaviour, redox state, absorption mechanisms,
etc. I don't think it's fair to make generalisations yet. We don't fully
understand which antioxidants work best when and under what conditions.
But broadly speaking I think dietary antioxidants (as opposed to
dedicated pills) are still looking good, and perhaps some pills work, I
don't know.

Of course, I'm biased, because my diet's full of 'em and I don't want
them to be bad for me!

On 09/02/14 18:22, Cathal Garvey wrote:
> Arsenic is an important micronutrient.
>
> On 09/02/14 16:05, David Murphy wrote:
>>> It's hard to believe any of this as absolute truth, because nutrition
>>> has a very wide scope, and depends on your genetics and epigenetics.
>>> So what's true for one person isn't for another living in similar
>>> conditions.
>>
>>
>> Sure and arsenic might be super good for just you and nobody else.
>>
>> It's been known for a long time that antioxidants weren't good for your
>> health (the health food market and popular culture was about 20 years
>> behind the times on that one). Trials to test if antioxidants were good for
>> your health had to be stopped because so many additional people were dying.

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[Jeff Backstrom]

A little late to the party, but the cite would be NEJM from 1996: May 2;334(18):1150-5. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease.

http://www.ncbi.nlm.nih.gov/pubmed/8602180

Ended 21 months early.

Note the fishing expedition part: relative risk of lung cancer was 1.28 (meaning 28% higher than expected) with a CI of 1.05 to 1.57 and a weak P-value by today's standard. There were no other statistically significant increases in other cancers.

But if you look at 73,135 person-years and chart all their cancers, SOMETHING will show up with a high incidence rate. That's just statistics for you. That's how we end up with studies that show (for example) a certain statin has no benefit in men, but a 10% benefit in (say) Hispanic women. You run enough numbers through the wringer, and you'll find SOME group stands out. Before long, you're finding some obscure cancer drug works astoundingly well in left-handed blind dentists.

[David Murphy]

>Really ? Do you have sources about that ?

http://www.goodreads.com/quotes/735647-two-large-trials-of-antioxidants-were-set-up-after-peto-s
Two groups of people at high risk of lung cancer were studied: smokers, and people who had been exposed to asbestos at work. Half were given 3-carotene and vitamin A, while the other half got placebo. Eighteen thousand participants were due to be recruited throughout its course, and the intention was that they would be followed up for an average of six years; but in fact the trial was terminated early, because it was considered unethical to continue it. Why? The people having the antioxidant tablets were 46 per cent more likely to die from lung cancer, and 17 per cent more likely to die of any cause,* than the people taking placebo pills. 

http://www.ncbi.nlm.nih.gov/pubmed/15572756

The Beta-Carotene and Retinol Efficacy Trial (CARET) tested the effect of daily beta-carotene (30 mg) and retinyl palmitate (25,000 IU) on the incidence of lung cancer, other cancers, and death in 18,314 participants who were at high risk for lung cancer because of a history of smoking or asbestos exposure. CARET was stopped ahead of schedule in January 1996 because participants who were randomly assigned to receive the active intervention were found to have a 28% increase in incidence of lung cancer, a 17% increase in incidence of death and a higher rate of cardiovascular disease mortality compared with participants in the placebo group.

[David Murphy]

to add some more recent work:

http://www.nature.com/news/antioxidants-speed-cancer-in-mice-1.14606

Supplemental effects

Bergö and his colleague, Per Lindahl, also a molecular biologist at the University of Gothenburg, stumbled into the antioxidant debate accidentally. The team was conducting unrelated experiments in mice that were genetically engineered to develop lung cancer, and decided to dose the mice with NAC as a control. If anything, they thought that NAC might slow the tumours slightly, says Lindahl. Instead, the control tumours grew three times faster than expected. “The real experiment turned out to be a disappointment,” he says. “But the control was quite interesting.”

The team decided to dig deeper, and expanded its study to include another common antioxidant, vitamin E. The researchers fed either NAC or vitamin E to the mice, using doses of 5 or 50 times higher than the daily recommended amount for mice. Human dietary supplements often have 4 to 20 times the recommended daily intake of vitamin E for humans, says Lindahl. The results for the two antioxidants were similar: tumours grew about three times faster than those in animals that did not receive the treatment. Treated mice also died from their cancers about twice as quickly as untreated mice.

[Jonathan BISSON]

David Murphy <murphy...@gmail.com> writes:

>>Really ? Do you have sources about that ?
> http://www.goodreads.com/quotes/735647-two-large-trials-of-antioxidants-were-set-up-after-peto-s
> Two groups of people at high risk of lung cancer were studied: smokers, and
> people who had been exposed to asbestos at work. Half were given 3-carotene
> and vitamin A, while the other half got placebo. Eighteen thousand
> participants were due to be recruited throughout its course, and the
> intention was that they would be followed up for an average of six years;
> but in fact the trial was terminated early, because it was considered
> unethical to continue it. Why? The people having the antioxidant tablets
> were 46 per cent more likely to die from lung cancer, and 17 per cent more
> likely to die of any cause,* than the people taking placebo pills.
>
> http://www.ncbi.nlm.nih.gov/pubmed/15572756
> The Beta-Carotene and Retinol Efficacy Trial (CARET) tested the effect of
> daily beta-carotene (30 mg) and retinyl palmitate (25,000 IU) on the
> incidence of lung cancer, other cancers, and death in 18,314 participants
> who were at high risk for lung cancer because of a history of smoking or
> asbestos exposure. CARET was stopped ahead of schedule in January 1996
> because participants who were randomly assigned to receive the active
> intervention were found to have a 28% increase in incidence of lung cancer,
> a 17% increase in incidence of death and a higher rate of cardiovascular
> disease mortality compared with participants in the placebo group.
>
>

All of that is interesting but:
They are taking tablets so:
- What are the excipients
- What is the purity of the "antioxydants". Working in a phytochemistry
lab that is concerned by this question, I can tell you that the 99.9%
purity advertised is almost NEVER the case. And when you have a 95%
purity on 30mg of something, it's still 1.5mg of … something … which we
may hope it's water… Well it's not just that… And I don't talk about
mixtures of compounds advertised as a single compound because the
analytical technique used can't discriminate between them. It's like,
hey here is a nice mattress… Oh and I have 0.01% bed bugs inside it, but
it's nothing .01% tsss…
- What about the matrix effect ? Taking a pure compound from a dry
tablet is not the same matrix as taking it from food. The pH is not the
same, the sugar/lipids content is not the same (modifying
absorption/release in the gut… hey wait a minute…). And what about the
effect of the tablet on smokers ? You have all the previous elements,
someone smokes, where are the compounds and excipients ? still in his
mouth, in his gut ?

[David Murphy]

>What are the excipients

this is the sort of criticism which could be applied to every trial ever for anything and leaves me thinking of a certain episode of "yes minister"

Sir Humphrey: In stage two you go on to discredit the information you’re not publishing.
Jim Hacker: How, if you’re not publishing it?
Sir Humphrey: It’s much easier if it’s not published. You do it by press leaks. Say it leaves some important questions unanswered, that much of the evidence is inconclusive, that the figures are open to other interpretations, that certain findings are contradictory and that some of the main conclusions have been questioned.
Jim Hacker: Suppose they haven’t?
Sir Humphrey: Then question them. Then they have.
Jim Hacker: But to make accusations like that you’d have to go through it with a fine-toothed comb.
Sir Humphrey: Nonsense – you can say all that without reading it. There are always some questions unanswered.
Jim Hacker: Such as?
Sir Humphrey: The ones that weren’t asked.

Lets just jump straight to the Cochrane Review

http://summaries.cochrane.org/CD007176/antioxidant-supplements-for-prevention-of-mortality-in-healthy-participants-and-patients-with-various-diseases

The present systematic review included 78 randomised clinical trials. In total, 296,707 participants were randomised to antioxidant supplements (beta-carotene, vitamin A, vitamin C, vitamin E, and selenium) versus placebo or no intervention. Twenty-six trials included 215,900 healthy participants. Fifty-two trials included 80,807 participants with various diseases in a stable phase (including gastrointestinal, cardiovascular, neurological, ocular, dermatological, rheumatoid, renal, endocrinological, or unspecified diseases). A total of 21,484 of 183,749 participants (11.7%) randomised to antioxidant supplements and 11,479 of 112,958 participants (10.2%) randomised to placebo or no intervention died. The trials appeared to have enough statistical similarity that they could be combined. When all of the trials were combined, antioxidants may or may not have increased mortality depending on which statistical combination method was employed; the analysis that is typically used when similarity is present demonstrated that antioxidant use did slightly increase mortality (that is, the patients consuming the antioxidants were 1.03 times as likely to die as were the controls). When analyses were done to identify factors that were associated with this finding, the two factors identified were better methodology to prevent bias from being a factor in the trial (trials with ‘low risk of bias’) and the use of vitamin A. In fact, when the trials with low risks of bias were considered separately, the increased mortality was even more pronounced (1.04 times as likely to die as were the controls). The potential damage from vitamin A disappeared when only the low risks of bias trials were considered. The increased risk of mortality was associated with beta-carotene and possibly vitamin E and vitamin A, but was not associated with the use of vitamin C or selenium. The current evidence does not support the use of antioxidant supplements in the general population or in patients with various diseases.

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[Cathal Garvey]

"The trials appeared to have enough statistical similarity that they
could be combined."

ALARM ALARM ALARM

I discard most "metastudies" if they can't immediately convince me
they're not a fishing expedition. Do they have an entire paper chapter
devoted to "all the studies we didn't incorporate"?

When presented with a corpus of research data that you propose a
"metastudy" of, if you want a certain answer you can trivially (and
crucially *unconsciously*) choose just the studies that, by
statistically irrelevant chance variance, will present the answer you
want when considered in aggregate.

This method is used by unscrupulous drug manufacturers all the time; as
they are not required (yet) to release *all* of their trials for
assessment by the FDA etc., they instead release the fraction of their
trials that support their assertion of benefit, and withhold the others.

Say you want to prove your coin flip can cure cancer. Trivial; just
release the trial data where flipping heads lead to better patient
outcomes, and disregard the rest. Same for a "meta-analysis" of studies
examining coinflips which all get different results; you can
deliberately or inadvertently (due to confirmation bias) disqualify
studies that disagree with your hypothesis and get *great, solid*
statistical answers that support it.

On 22/02/14 00:43, David Murphy wrote:
>> What are the excipients
>
> this is the sort of criticism which could be applied to every trial ever
> for anything and leaves me thinking of a certain episode of "yes minister"
>

> *Sir* *Humphrey*: In stage two you go on to discredit the information
> you're not publishing.
> *Jim* *Hacker*: How, if you're not publishing it?
> *Sir* *Humphrey*: It's much easier if it's not published. You do it by

> press leaks. Say it leaves some important questions unanswered, that much
> of the evidence is inconclusive, that the figures are open to other
> interpretations, that certain findings are contradictory and that some of
> the main conclusions have been questioned.

> *Jim* *Hacker*: Suppose they haven't?
> *Sir* *Humphrey*: Then question them. Then they have.
> *Jim* *Hacker*: But to make accusations like that you'd have to go through

> it with a fine-toothed comb.

> *Sir* *Humphrey*: Nonsense - you can say all that without reading it. There

> are always some questions unanswered.

> *Jim* *Hacker*: Such as?
> *Sir* *Humphrey*: The ones that weren't asked.

>
> Lets just jump straight to the Cochrane Review
>
> http://summaries.cochrane.org/CD007176/antioxidant-supplements-for-prevention-of-mortality-in-healthy-participants-and-patients-with-various-diseases
>

> The present systematic review included *78 randomised clinical trials*. In

> total, 296,707 participants were randomised to antioxidant supplements
> (beta-carotene, vitamin A, vitamin C, vitamin E, and selenium) versus
> placebo or no intervention. Twenty-six trials included 215,900 healthy
> participants. Fifty-two trials included 80,807 participants with various
> diseases in a stable phase (including gastrointestinal, cardiovascular,
> neurological, ocular, dermatological, rheumatoid, renal, endocrinological,
> or unspecified diseases). A total of 21,484 of 183,749 participants (11.7%)
> randomised to antioxidant supplements and 11,479 of 112,958 participants
> (10.2%) randomised to placebo or no intervention died. The trials appeared
> to have enough statistical similarity that they could be combined. When all
> of the trials were combined, antioxidants may or may not have increased
> mortality depending on which statistical combination method was employed;
> the analysis that is typically used when similarity is present demonstrated
> that antioxidant use did slightly increase mortality (that is, the patients
> consuming the antioxidants were 1.03 times as likely to die as were the
> controls). When analyses were done to identify factors that were associated
> with this finding, the two factors identified were better methodology to
> prevent bias from being a factor in the trial (trials with 'low risk of
> bias') and the use of vitamin A. In fact, when the trials with low risks of
> bias were considered separately, the increased mortality was even more
> pronounced (1.04 times as likely to die as were the controls). The
> potential damage from vitamin A disappeared when only the low risks of bias
> trials were considered.

> *The increased risk of mortality was associated with beta-carotene and

> possibly vitamin E and vitamin A, but was not associated with the use of
> vitamin C or selenium. The current evidence does not support the use of
> antioxidant supplements in the general population or in patients with

> various diseases.*

>> purity on 30mg of something, it's still 1.5mg of ... something ... which we
>> may hope it's water... Well it's not just that... And I don't talk about

>> mixtures of compounds advertised as a single compound because the
>> analytical technique used can't discriminate between them. It's like,

>> hey here is a nice mattress... Oh and I have 0.01% bed bugs inside it, but
>> it's nothing .01% tsss...

>> - What about the matrix effect ? Taking a pure compound from a dry
>> tablet is not the same matrix as taking it from food. The pH is not the
>> same, the sugar/lipids content is not the same (modifying

>> absorption/release in the gut... hey wait a minute...). And what about the

>> effect of the tablet on smokers ? You have all the previous elements,
>> someone smokes, where are the compounds and excipients ? still in his
>> mouth, in his gut ?
>>
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>> Groups DIYbio group. To post to this group, send email to
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[David Murphy]

>When presented with a corpus of research data that you propose a
>"metastudy" of, if you want a certain answer you can trivially (and
>crucially *unconsciously*) choose just the studies that, by
>statistically irrelevant chance variance, will present the answer you
>want when considered in aggregate.

Are you not familiar with the methods of a proper systematic review?

They're specifically designed to deal with that exact problem.

Further ,this isn't just any review. it's a cochrane review, they're pretty much the gold standard for such things.

>Do they have an entire paper chapter devoted to "all the studies we didn't incorporate"?

pretty much, you can read all their criteria. 

http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD007176.pub2/full

The criteria were all specified in advance along with the criteria for categorising  trials as more or less likely to be biased.

It was a Cochrane review which got the ball rolling on dragging Roche over the coals over missing Tamiflu trial data.
http://www.pharmatimes.com/article/12-11-14/Sue_Roche_over_Tamiflu_data_says_Cochrane.aspx

Those same drug manufacturers you talk about own most of the companies selling the antioxidant pills.
It's their marketing you've fallen for.

[Cathal Garvey]

I haven't "fallen" for anything; I get my vitamins from a good and
varied diet. I'm just skeptical of claims that isolated nutrients can
cause or exacerbate cancer; it's a big claim, requiring big evidence.

Good to hear the review established criteria in advance, sounds well put
together. So I'll give it a little more credit, but I'll be slow to jump
on the bandwagon, yet. Supplements being "ineffective" is something I'm
acutely familiar with, as b12 is barely absorbed from the conventional
tablet, as is resveratrol, etc. etc., but "harmful in normal dose" will
take some convincing.

[David Murphy]

depends what you mean by "normal" and plenty of utterly essential nutrients have known negative health effects at high doses.

Finding negative effects at doses of 5 or 50 times higher than the daily recommended amount isn't that surprising but is very relevant when supplements can have 4 to 20 times the recommended daily intake.

I'm guessing that any effects would be negligible to the point of not mattering at the sorts of levels you'd get from just eating normal fresh food but may be relevant to people who feed their children supplements every day thinking they're doing them good.