Death by supplements

The annoying death crud that has gripped me continues apace. Fortunately, I happen to have a rather interesting guest blog post that I've had lying around a while, and now seems like the perfect time to use it. It comes from Dr. Arnon Krongrad, an expert in prostate cancer and minimally invasive surgery. I'm publishing it because he has a rather interesting observation about the use of supplements and how it may contribute to the development of aggressive prostate cancer. Here is Dr. Krongrad's contribution:

What would you pay to have erections? Would you pay with your life? A report from Texas suggests that in some cases maybe you might. The report focuses on two men who developed aggressive prostate cancer after taking over-the-internet supplements. What is the risk?

In a day of pomegranate, lycopene, and other magic potions that "may" help you, the realities are: 1) the supplement industry is largely unregulated and 2) the Institute of Medicine and the Food and Drug Administration have found that health claims are largely unsupported, and 3) supplement use can be associated with death. The cancer supplement PC-SPES, which was spiked with the blood thinner warfarin, is a recent example. With supplements, the risk may be as real as the temptation.

Let's examine two stories related to prostate cancer. One comes from the tightly controlled world of clinical trials. The other comes from the more tolerant world of online commerce.

In 1996, my colleagues and I published a study on selenium in prostate cancer prevention. In brief, we found an unprecedented 60% reduction of prostate cancer in men who received dietary supplements of selenium. Our study was imperfect and while it produced an interesting hypothesis - selenium reduces prostate cancer incidence - it had not been designed to give a definitive answer. Last year, a National Cancer Institute report found that selenium supplementation is associated with more aggressive prostate cancer and prostate cancer death. In other words, despite the hope given by our imperfect 1996 study, it may actually be that selenium supplements accelerate prostate cancer.

Doctors in Texas have now reported that two men developed aggressive prostate cancer after taking the same herbal supplement which they bought over the internet; they reportedly later died of prostate cancer. They had bought the supplement to improve muscle strength and sexual vigor. Both had had normal prostate examinations in the not-so-distant past. Both had unusually aggressive clinical courses. Laboratory analysis of the supplements revealed unlisted ingredients, including testosterone, and potent cancer-cell promoting properties of these supplements. The FDA has now become involved and the supplements have been taken off the market. But what about all the other supplements still available? What's in them? We cannot easily know.

We have not yet identified a way to prevent prostate cancer. It may be that we have instead identified means to accelerate prostate cancer. Before you start to take supplements, see if they are being promoted as something that "may" provide a result. If they are, be careful. You want something that "will" provide a result, as proved with appropriately designed trials. As you'll soon discover, products proven to provide results are rare. As shown, things that "may" help you "may" hurt you too.

Guest blogger Arnon Krongrad, MD is Medical Director of the Krongrad Institute for Minimally Invasive Prostate Surgery. He is Chairman of the Prostate Cancer Mission and Author of "Behind the Mask," essays on prostate problems and more.

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Years ago I attended a presentation of a study on black cohosh for treatment of prostate cancer. The preliminary data indicated such a striking response that the authors became a little suspicious and sent the black cohosh, donated by a supplements and herbal company, for analysis. Results: the black cohosh came back with trace amounts of flutamide or some similar testosterone antagonist (my notes were lost in a recent office move).

I know someone who takes lots of muscle building supplements on the grounds that, even if they don't work, they do no harm. I have absolutely no idea whether glutamine or whey protein have been shown to have negative effects, or whether they go "straight through".

In the absence of clear evidence in the case of a lot of supplements that they do harm, it might be useful to have a database of supplements that are almost certainly safe - even if completely uneffective.

It might include those that are safe unless you take ludicrously large amounts - like Vitamin A.

Personally I can't see the point of healthy people taking supplements at all, but such a list might be useful to those who just want to know what won't hurt them,

BTW, "Annoying Death Crud" sounds just like a thrash metal band.

I know someone who takes lots of muscle building supplements on the grounds that, even if they don't work, they do no harm. I have absolutely no idea whether glutamine or whey protein have been shown to have negative effects, or whether they go "straight through".

In the absence of clear evidence in the case of a lot of supplements that they do harm, it might be useful to have a database of supplements that are almost certainly safe - even if completely uneffective.

It might include those that are safe unless you take ludicrously large amounts - like Vitamin A.

Personally I can't see the point of healthy people taking supplements at all, but such a list might be useful to those who just want to know what won't hurt them,

BTW, "Annoying Death Crud" sounds just like a thrash metal band.

Ah, we can tell it was a guest post. I scrolled down to get to the meat of the article, and found I was past the comments.

Excellent reminder of a number of important points: just because it's "natural" doesn't mean it's safe; we don't have the first clue what we're doing when we take supplements; medicinals that are not regulated by the FDA may not be the safest things in the world.

I have an album by Annoying Death Crud. It's only available on vinyl, though. I have to buy one of those conversion deals to get it onto my iPod!

Kapitano, I can answer that, somewhat. Whey protein is one of those "perfect" foods. High in essential amino acids, easily flavored, yada yada yada. Depending on the grade and source, it can be very high in cholesterol.

Glutamine isn't likely to be especially toxic to most people, but it won't do much good, as the body doesn't do much with high doses of one amino acid, doing much better with amino acids from food.

It is always possible that there is a small part of the population that is sensitive to large doses of certain amino acids, such as L-tryptophan. Fine for most people, but a supplement dose in some people will cause a pretty nasty systemic and irreversible dysfunction. It was supposed to be outlawed as a supplement decades ago, but is still available, due to clever PR and well placed political allies to the supplement industry. Senator Orrin Hatch (R-Utah) is beholden to supplement pushers, as many are based in Utah, and many people living in Utah are big into supplements (especially Mormons). He himself believes that his vitamins keep him well, and makes regular woo filled statements to that effect.

Creatine, taken properly, will cause an increase in muscle mass, but only because creatine associates with muscle tissue and draws water with it. The greatest risk for creatine use is dehydration. This is especially true for competitive bodybuilders, who dehydrate before a show in order to improve muscle definition. Once you stop using creatine (typically used 1 month on, 1 month off), you go back to normal.

Zinc is very important to muscle building, but if you take a multivitamin and eat a balanced diet, you get all you need. Get over 50 mg per day and you get into a range that causes neurotoxic dysregulation of copper uptake (copper is a trace mineral required for proper brain function). A quick search of one of the big supplement stores showed that they carry three sizes. 30, 50 and 100. 30 plus most multivitamins gives you 45, and with most diets giving you 10-15, its easy to get in trouble. Only people with specific conditions and doctor's instructions should ever use high zinc doses.

By Robster, FCD (not verified) on 25 Mar 2008 #permalink

Probably should mention that 15mg is a good daily intake for zinc, and toxic effects don't show until you pass 50mgs. So a balanced diet plus a multivitamin gives you 25-30mgs which is well within the safe use window.

By Robster, FCD (not verified) on 25 Mar 2008 #permalink

Annoying death crud is pandemic in the U.S. at present, and the failure of the media to report on it is reminiscent of the Chinese suppression of the emergent SARS epidemic in 2003.

By Alec Campbell (not verified) on 26 Mar 2008 #permalink

Just another MD telling half truths. Putting all "supplements" in the same bucket is about as intelligent as putting all "drugs" in the same category. And this is exactly the sort of anecdotal evidence that MD's like to get high and mighty about when it suggests benefit, though they seem to have no problem with weak anecdotes when it might serve their need to resort to scare tactics. Oooohhh supplements are scary, trust your doctor, he can sell you a nice petrochemical, err, drug, with side effects even he can't count or articulate.

We need a new system of health, the one we have has made the term Medical Science an oxymoron.

Whey shouldn't really be considered a supplement. It's a food and it's in all dairy products that haven't specifically had it separated out like cheese. A glass of milk is roughly half whey.

Personally, I think fresh whey from fresh yogurt is far better than powdered formulations, but the latter should be no more harmful than drinking powdered milk. Indeed, powdered milk does include both the whey and the casein and is a great starting medium for yogurt from which you can extract the whey.

There are growth factors in whey as well as a wide range of mostly uncharted peptides, proteins and enzymes but the same is true for milk which immediately separates into whey in your stomach. One way that mother's milk differs from cow's milk is that is has a larger whey fraction. Now does that sound dangerous?

The study you cited in regards to selenium increasing the risk of prostate cancer actually only saw a tenable increased risk in men who took multivitamins more than seven days a week. Certainly the multivitamins contained some selenium, but to say the study shows a tenable increased risk for selenium is confounded by the dozens of other vitamins and minerals in these pills. Moreover, finding an increased risk in people who take more than seven multivitamins a week does not strike me at all as being a tenable enough risk to warrant a warning for the general population as those of us who take more than 7 multivitamins a week are probably a self selected bunch and might ALREADY HAVE advanced prostate cancer.

I'm not saying Selenium is some sort of wonder supplement at all, indeed selenium can be dangerous. But you seem to be apply a double standard in your citations' rigor.

The study you cited in regards to selenium increasing the risk of prostate cancer actually only saw a tenable increased risk in men who took multivitamins more than seven days a week. Certainly the multivitamins contained some selenium, but to say the study shows a tenable increased risk for selenium is confounded by the dozens of other vitamins and minerals in these pills. Moreover, finding an increased risk in people who take more than seven multivitamins a week does not strike me at all as being a tenable enough risk to warrant a warning for the general population as those of us who take more than 7 multivitamins a week are probably a self selected bunch and might ALREADY HAVE advanced prostate cancer.

I'm not saying Selenium is some sort of wonder supplement at all, indeed selenium can be dangerous. But you seem to be apply a double standard in your citations' rigor.

The "supplement" PC-SPES containes diethylstilbestrol (DES), which is a synthetic estrogen; indomethacin, a potent anti-inflammatory drug; and warfarin. It's not a "supplement" if it has a drug in it & synthetic compounds. It's a drug. What is Warfarin? Warfarin was originally a rat poison. It killed rats by causing internal hemorrhaging/bleeding. If you poison yourself only a little, you get blood that doesn't clot so easily. Nice blood thinner.

I guess the author has no clue that properly prescribed & taken FDA approved drugs is the single biggest killer in the US.
Drugs tested in these FDA approved clinical trials are isolated. They often do not test for interaction with other drugs. Most trials run 3-6 weeks. No long term testing is done. Countless times it has been proven the drug manufacturers bury bad test results & offer up the few that show even the most marginal success. Then ta da! They have a new drug to push on the sheeple. The FDA is the pimp of Big Pharma, period. Learn about it here: http://www.naturalnews.com/022282.html

A hand full of blueberries has been proven to be more effective at lowering cholesterol than ANY statin drug on the market. But guess what? No one can patent blueberries, so you never hear about it. No patents, no profits for big pharma. Wake up sheeple!

This makes no sense, the cause for the cancer can also be attributed to anything else that was found in both of the people. Testosterone, I'm looking at you.

I heard this claim by a few of the trolls on this blog:

"I guess the author has no clue that properly prescribed & taken FDA approved drugs is the single biggest killer in the US."

What real evidence is that based on or is it just a flat out "Big pharma conspiracy" lie? I am willing to guess it's just a massive logical fallacy whereas a person dies of a disease, such as cancer, after being on medicine, such as chemo, so it wasn't the cancer but it was the chemo that killed the person.

It has been documented ozzy, that improperly prescribed, improperly administered and sometimes inadequately tested pharmaceticals take thousands of lives every year. But don't take my word for it, read up about it from the AMA or any notable medical journal. Its common knowledge.

Supplements also have similar issues when improperly manufactured, over used or taken by children. However the numbers of incidents are much smaller. This because, supplements are much less used than pharmaceticals.

So the safety numbers cannot really be compared. My belief is that users of supplements are generally more healthy and using less pharmaceticals than the overall population.

Orac, as you may know, supplments are forbidden from making any medical claims without using the word 'may'. I can't even sell a pill containng water without legally saying water "may" be necessary for sustaining life.

This article has the scent of propaganda.

As we have seen in the past, big pharma interests have made war with the supplment business. Large money attempting to take away consumer rights to line their pocketbooks with over prescribed medicines that have enormous social and economic costs on our nation.

jo jo said "But don't take my word for it, read up about it from the AMA or any notable medical journal. Its common knowledge.'

Um, not really. There are death statistics that show up to about age 45 or so, the main cause of death are accidents (primarily vehicular), and then after age 45 it is heart failure and cancer. From:
http://www.disastercenter.com/cdc/

How about you show us the papers that show that "common knowledge"?

JoJo,

The dietary supplement business is a $21 billion a year industry and that doesn't include the various alternative health "education" books on the market. Supplement manufacturers and distributors are not doing it out of the kindness of their heart. They are not non-profit orgs but instead are just out to make a buck by capitalizing on the lack of scientific understanding in the general public. So let me alter your quote:
"Large money attempting to fool consumers to line their pocketbooks with 'medicines/placebos' that have little to no scientific evidence of efficacy with real economic costs on our nation."

Did you hear that three men who ate beef also got prostate cancer? If anything proves that's where cancer comes from it's that totally meaningless coincidence. Let write more, ahem, "Articles" about how two people with cancer prove stuff. Americans are stupid as hell about science anyhow, they'll click it and our advertisers will be happy. This just in!!! Two brunettes got colds!!! coincidence or proof of an alien invasion?!!!

By vapor articles suck (not verified) on 26 Mar 2008 #permalink

Dear colleagues,

It is understandable that we get worked up about the very few deaths associated with dietary supplements. But some points that Dr. Krongrad and some of the responders to his guest blog have made simply beg for some additional perspective. Please allow me to address some of these issues with relevant data from reputable sources:

1. Dr. Krongrad stated that the dietary "supplement industry is largely unregulated".
My response: This is not really a fair statement considering that recent regulatory efforts - supported by that same industry - have clamped down on the industry's freedom to operate outside the regulatory system. Drug and dietary supplement regulation are becoming more and more similar, though the safety records of the two types of products are remarkably distinct. The dietary supplement industry is now largely regulated, with more and more regulations closing the gaps. Indeed, the industry strongly supported the law to ban steroid precursors from being sold as dietary supplements, making all such products illegal drugs. And the 2006 passage of a law to require all serious adverse events to be reported to MedWatch within 3 weeks - now in effect - is an appropriate method of monitoring safety and determining problem areas needing increased monitoring or official action; though we should not confuse raw AERs with actual evidence of causes-and-effects. The implementation of the long-delayed current good manufacturing practices (cGMP) regulations (that were actually authorized by the oft-maligned DSHEA law in 1994) now requires all supplement manufacturers to be cGMP compliant over the next two years, but with the largest manufacturers required to follow that standard no later than this coming June (2008). cGMP regulations are forcing manufacturers to have quality controls on raw materials and finished goods throughout the manufacturing process, including identity and safety testing. The FDA already prohibits all adulterated products, and has in fact used its authority to act against known offenders, as noted elsewhere in this blog. (http://scienceblogs.com/insolence/2008/03/death_by_supplements.php).

2. Dr. Krongrad states that "the Institute of Medicine and the Food and Drug Administration have found that supplement health claims are largely unsupported".
My response: The FDA clearly regulates supplement label claims and requires manufacturers to submit all label claims and maintain proper documentation. The agency apparently does not review this information unless there is a problem; meanwhile making manufacturers submit such information to it while requiring a contradictory label disclaimer that the FDA has not reviewed the claims. I guess that's what's called "plausible deniability". However, the vast majority of responsible manufacturers are careful to present adequate documentation to the FDA, and the cGMP regulations require well-documented justification of all processes, including the writing of label claims. DSHEA requires preapproval of all new dietary supplement ingredients with an eye to proving safety, though manufacturers are allowed to use existing ingredients if they first submit their new label claims to the agency. All new drugs need pre-approval, as do all new supplement ingredients, but drugs are approved for specific uses (though often used for other unapproved "off label" conditions) while supplements are not allowed to make any disease claims, with very few exceptions for FDA-approved health claims. (http://www.cfsan.fda.gov/~dms/supplmnt.html)

3. Dr. Krongrad states that "supplement use can be associated with death".
My response: Supplements, foods and drugs are all associated with death risks, with supplements statistically being the safest of them all, by far. Some have chosen to focus on a very few cases of dietary supplements possibly linked to deaths, but other readers have mentioned the very large death toll from both properly prescribed drugs and drug errors as a way to counter the thinking that drugs are somehow more tightly regulated, and thus presumably safer, than dietary supplements. I agree. In the annals of our peer-reviewed literature, dietary supplements are rarely responsible for accidental deaths other than by illegal adulteration, making this class of products far safer than less-regulated foods or even more regulated drugs. And, just as in the case of prescription drugs, the FDA does not test for purity and safety. Regulators routinely require industries to have quality controls in place to do such testing themselves, with penalties for non-compliant products that come to the attention of the regulatory agencies. And it is appropriate that regulators focus on the products with the most potential to cause injuries, illnesses and deaths. The routine collection of serious AERs will serve to focus the regulators on problem areas. (For more discussion and literature citations, see #7 below.)

Other issues:

4. Dr. Krongrad describes an adulterated dietary supplement associated with 2 deaths, claiming that "We cannot easily know" what's in supplements.
My response: cGMP manufacturers must test their ingredients, so responsible manufacturers do not allow the use of adulterated ingredients and have means to avoid them. It is likely that the adulterant in this case was deliberately added to ensure a noticeable effect. By definition, an adulterated supplement actually becomes an unlabeled illegal drug, not a dietary supplement. There are already penalties for such adulteration under current regulations, and Dr. Krongrad has noted that the FDA has forcefully removed these products from the market. The solution is for cautious consumers to purchase their dietary supplements from responsible brands that have third-party quality certifications, and it is likely that only those individuals seeking foolish shortcuts will be involved with mail order brands of questionable integrity. The vast majority of supplement manufacturers wish to promote natural health and will not risk their companies on such questionable unlawful schemes.

5. There were several comments about zinc toxicity.
My response: The NIH Office of Dietary Supplements reports that while 40 mg daily is the upper limit, the toxicity and imbalance issues typically manifest only at levels over 150 mg/day. (http://ods.od.nih.gov/factsheets/cc/zinc.html)

6. JoJo posted a comment that "Supplements also have similar issues when improperly manufactured, over used or taken by children. However the numbers of incidents are much smaller. This because, supplements are much less used than pharmaceticals [sic]."
My response: A recent survey reports that, "43 percent of Americans say they take a daily multi-vitamin for cancer protection. 21 percent take some other form of nutritional or dietary supplement." (http://www.icrsurvey.com/Study.aspx?f=Supplement_survey_release.html) This indicates that a majority of Americans, about 2/3, take dietary supplements. In the case of prescription drugs, about 45% of Americans take a prescription, with the percentage rising sharply with age. (http://www.cdc.gov/nchs/fastats/drugs.htm) And Americans also take non-prescription OTC drugs, with a combined rate of drug use estimated at about 2/3 of all Americans...about the same percentage of the population as uses dietary supplements. So JoJo's argument that the use rates are sharply different is not substantiated by the data, meaning that the dramatically lower death and adverse event rates for dietary supplements are indeed a valid testimony to their relative safety versus drugs.

7. David Loeb posted a comment that "just because it's "natural" doesn't mean it's safe" and "medicinals that are not regulated by the FDA may not be the safest things in the world".
My response: There are no medicinals that are unregulated by the FDA, and most natural products are far safer than artificial ones. Most synthetic substances, including drugs, have a far greater risk of side effects and deaths in the clinical literature. Still, we make choices every day and do not stop consuming most foods, drugs or supplements because most have such a tremendous reward-to-risk ratio. We obviously can't stop eating. And since our diets are known to be deficient in essential nutrients, dietary supplements do have an important role to play in ensuring adequate nutrition. (Nutrition and Your Health: Dietary Guidelines for Americans. USDA. 2005. also Fairfield KM, Fletcher RH. Vitamins for chronic disease prevention in adults: scientific review. JAMA. 2002 Jun 19;287(23):3116-26. Review. Erratum in: JAMA 2002 Oct 9;288(14):1720. PMID: 12069675) It was reported in JAMA that, "Most people do not consume an optimal amount of all vitamins by diet alone. Pending strong evidence of effectiveness from randomized trials, it appears prudent for all adults to take vitamin supplements." (Fairfield KM, Fletcher RH. Vitamins for Chronic Disease Prevention in Adults: clinical applications. JAMA. 2002;287:3127-3129.)

Regarding food safety, a medical journal report concluded that, "We estimate that foodborne diseases cause approximately 76 million illnesses, 325,000 hospitalizations, and 5,000 deaths in the United States each year." (Mead PS, et al. Food-related illness and death in the United States. Emerg Infect Dis. 1999 Sep-Oct;5(5):607-25. Review. PMID: 10511517). This indicates that eating food is a far riskier activity than taking dietary supplements, since the risk for the 2/3 of food eaters that are also supplement takers is literally orders of magnitude lower than 2/3 of the known risk of eating food (which everyone does). There are few human activities with lower odds of causing death or serious illness than taking dietary supplements.

In fact, even lipsticks and cosmetics are typically responsible for more annual accidental deaths than vitamins. Looking at the categories of deaths reported by the American Association of Poison Control Centers from 2002-2004, only 5 accidental deaths were reported linked to dietary supplements, 7 from cosmetics and personal care items, over 600 related to acetaminophen use, 117 related to aspirin use, and 66 from ordinary household cleaners. By far, dietary supplements are probably the safest category of products that we put into our mouths, and are demonstrably getting safer with the new regulations now being implemented.

8. Let's talk about the real dangers of drugs, which exceed the risks of supplementation by mind-boggling amounts. That is the main reason why drugs are controlled substances. Here is the citation for the JAMA report discussed elsewhere in this blog, documenting the large death toll for properly prescribed drugs: "We estimated that in 1994 overall 2,216,000 (1,721,000-2,711,000) hospitalized patients had serious ADRs and 106,000 (76,000-137,000) had fatal ADRs, making these reactions between the fourth and sixth leading cause of death." (Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA. 1998 Apr 15;279(15):1200-5. PMID: 9555760)

Also, the Washington Post reported (7/21/06) on an Institute of Medicine study released a day earlier on the toll of improperly prescribed drugs: "At least 1.5 million Americans are sickened, injured or killed each year by errors in prescribing, dispensing and taking medications, the influential Institute of Medicine concluded in a major report released yesterday. Mistakes in giving drugs are so prevalent in hospitals that, on average, a patient will be subjected to a medication error each day he or she occupies a hospital bed, the report by a panel of experts said. Following up on its influential 2000 report on medical errors of all kinds, the institute, a branch of the National Academies, undertook the most extensive study ever of medication errors in response to a request made by Congress in 2003 when it passed the Medicare Modernization Act. The report found errors to be not only harmful and widespread, but very costly as well. The extra expense of treating drug-related injuries occurring in hospitals alone was estimated conservatively to be $3.5 billion a year."

Prescription drugs were named as one of the largest causes of American deaths, perhaps the second largest, as noted in another report by CDC, also published in JAMA:

"IN 2004, POISONING WAS SECOND ONLY to motor-vehicle rashes as a cause of death from unintentional injury in the United States. Nearly all poisoning deaths in the United States are attributed to drugs, and most drug poisonings result from the abuse of prescription and illegal drugs. Previous reports have indicated a substantial increase in unintentional poisoning mortality during the 1980s and 1990s. To further examine this trend, CDC analyzed the most current data from the National Vital Statistics System. This report summarizes the results of that analysis, which determined that poisoning mortality rates in the United States increased each year from 1999 to 2004, rising 62.5% during the 5-year period." (FROM THE CENTERS FOR DISEASE CONTROL AND PREVENTION: Unintentional Poisoning Deaths--United States, 1999-2004. JAMA, March 28, 2007; 297: 1309 - 1311.)

As you see, the fuss about dietary supplement safety is in reality a tempest in a teapot, as the risks of eating normal foods and using pharmaceuticals are each far more dangerous, in turn. This is not to minimize the need for strict controls of dietary supplements...but to a large degree, these controls already exist or are currently being implemented. Enforcement has been slowly tightening over the past 15 years. But, looking at these authoritative death and injury statistics, is anyone really surprised that the FDA properly chooses to focus its enforcement actions on products that are proven to be dramatically more dangerous to public health than dietary supplements? Some form of triage is appropriate, given the large number of deaths and injuries from food and drugs. But dietary supplements generally do not significantly contribute to these risks, and therefore do not deserve to be singled out as especially dangerous when they are comparatively very safe.

Neil E. Levin, CCN, DANLA