for Side Effects of Creatine:
Will Hopkins (original message)
I have been writing a short item on the possibility that creatine might damage the kidneys of the occasional athlete. I found myself writing the following:
"Manufacturers of creatine--and of any other ergogenic aid that has not been properly assessed for risks to health--should consider an up-front warning along these lines: "Evidence to date does not allow us to exclude the possibility that use of this product has life-threatening consequences for perhaps one person in 1000" (or however many the manufacturer feels is justified on the basis of the available evidence)."
Would such a warning guarantee the manufacturer immunity from litigation by the one athlete in 1000 who does succumb to a serious side effect? I believe it ought to. Does anyone know how the courts in the US would handle it?
Don't know about the courts. But why did you pick 1/1000? I haven't seen any studies on groups larger than 30.
Sample size calculations for a side effect that occurs in 5% of control and 10% of intervention group suggest 474 people per group. That would mean side effects at the rate of 5/100 rather than 1/1000 for common things. If you take a side effect that is extremely rare in the population (<1/10000), and give the side effect in the intervention group a chance of 1/100, the numbers required are 1000 per group. If it occurs in 5/100 of the side effect group, you still need 190 people per group. At 10/100, you need 93 per group. Don't know of any studies this large. If you do, I'd love the references.
I just thought I would comment on what you said about creatine. To start, I am no legal person, but would tend to think it would be difficult. The reason is that the one athlete in a 1000 would have to be able to prove causality between the creatine and the health problem.
The other dilemma is that any athlete using creatine is very likely to have used other supplements as well and that can lead to an argument that it may not have been the creatine that caused the problem. You also mention about the manufacturer properly assessing the risk to health of the creatine, or any of their supplements; this assessing of risk for creatine, in my opinion, is quite a difficult thing, given that available evidence strongly suggests it is ok, and that it's been around for so many years. I have read some articles that made claims about many pro athletes taking creatine every day in training in "various" doses, meaning larger than what is prescribed in the loading/maintenance phases, basically like candy. I think the pharmaceutical industry works the same way with the "numbers". They do group tests (clinical trials) and arrive at their risk assessment by saying certain percentages had good, bad, or no effects...and yes, they get sued up the wazoo occasionally (e.g. phen-phen) when enough things go wrong.
Phen Phen is a diet and weight loss drug that was manufactured by a company called American Home Products in the States and was linked to heart problems (as best I remember). A class action suit (thousands of people acting on the same behalf) brought the company to court and won. It was an interesting case. I'm sure there are lots we don't hear about.
I don't think you will find the manufacturers putting labels on their stuff anytime soon, because the FDA (Food and Drug Admin) does not have enough control of their function; that's why there's so much crap on the market and so much advertising that is out of control. And let's not forget how cheap all the stuff is to make.
This sort of action could also be considered forcible on all the major food and drink companies to put similar statements on all their products which "may" contain allergens, which "may" ultimately lead to an individual's death. I think you will agree we won't be seeing this in the foreseeable future.
Your use of "possibility & creatine might" are the very reasons that no such labeling is required. At present there is no such evidence for the statements you are making. The FDA disclaimer is the first defense against such claims. Also, manufacturers could not pluck a figure out of the air; by doing so they would admit there is a problem associated with the use of creatine, and this would lead to a guaranteed ban on the product. I am sure your thoughts were to protect manufacturers, but in this case it would have the reverse effect.
I am not an attorney, but I have acted as an expert witness with regard to product warnings in the US.
First, nothing will guarantee a manufacturer immunity from litigation.
Second, you seem to suggest that the product (creatine), when used as intended, can result in the user's death. And you wonder if a warning would be sufficient to protect the manufacturer. I would draw your attention to the plight of the tobacco companies who relied on this tactic, and were successful for quite a while. However, that approach is no longer viable in the U.S.
Third, I would suggest you consult the human factors (or ergonomics) literature regarding the design of adequate warnings. Standards have been written. For example ANSI Z535, which was published in 1991, addresses the major issues of warning design. To try to design a warning in a vacuum when so much research has been done on how to design and how not to design a warning would probably result in a warning that did not meet minimum standards.
Fourth, a warning that has been placed on a product for the sole purpose of avoiding litigation, and not to provide protection to the product user, would be recognized by any judge or jury is a self-serving ploy. The warning should tell the user what the specific danger is (liver damage?) and how the user can avoid it short of not using the product at all (reduced dosages? periodic tests?).
When designing a warning think first of the user, not the manufacturer. What information would you want which would help you make a decision on whether (and how) to use a product. Then consult the literature on how to design that warning.
My GUESS is that any stated ratio would never sail in the US. This place is way nuts when it comes to litigation. All must be vague so the lawyers can fight it out and collect the spoils.
I am unsure of the how the courts in the US handle it with respect to manufacturers, but I would be extremely interested in how the US courts would view the manner in which the sport science community and sport scientist have whole heartedly promoted the widespread use of this compound without researching the harm that the use of these ergogenic aids may be causing.
Some time ago I was critical of the sportscience community for its preoccupation with validating and promoting the use of any substance or technique without first establishing that the use of such things would cause no harm.
I believe that a court may find that it is not the manufacturer who is to be held culpable but the researchers and sport scientists who advocate the use of techniques and substances without clearly determining the harmful affects first. With regard to creatine it is the sport scientists who determine the usage and the regimes and the benefits and completely ignore the harm that may be caused, the manufacturer just makes it.
There are many papers that explore the relationship of elevated creatine levels and diseases, as well as many others that examine the harmful affects of other compounds widely advocated by the sportscience community, perhaps a class action against those advocating high carbohydrate use and its cause of rampant dental decay.
Creatine phosphate has the ability to provide an energy source in the absence of oxygen, and obviously is important in contractile cells. Would such a metabolite also be useful in a rapidly growing tissue that may often outgrows its blood supply and yet still need to proliferate?
To repeat the above more clearly it may be the sportscience community that is causing the problem, not the manufacturers, they merely supply the market the sportscience community has developed.
We also can't exclude the possibility that the sugar water crap we give our athletes in the name of 'sports drinks' may be damaging their pancreas. To my knowledge, the evidence on these products so far has proven only two things: 1. That they improve endurance time to fatigue in submaximal activities (a result which cannot be generalized to other, high-intensity intermittent sports). 2. That they do not slow down gastric emptying or intestinal absorption if the solution is low enough (<8%).
I'm all for providing fluids and carbs during exercise. But for all we know we're setting our athletes up for type II diabetes with this stuff. In my opinion it's doubtful that any warnings will protect the manufacturer, school, or athletic staff if/when a determined lawyer sees this opportunity and starts making his case.
Just a thought. There's no evidence linking creatine with any health problems--in fact it may positively affect blood lipid profiles in trained athletes and hypertriglyceremic subjects, respectively [Kreider et al., Med. Sci. Sports Exer. 30(1): 73-82, 1998; Earnest et al., Clin. Sci. 91: 113-118, 1996]. The existing scientific literature suggests that up to 2 years of PCr or Cr administration is medically safe, and that weight gain is the only side effect. Until there's evidence linking it with life-threatening consequences, such a warning seems inappropriate.
Will, I do not specifically know the legal system here BUT I suspect that this type of warning would not provide protection. Reference the recent legal actions relative to tobacco. On the other hand, there must be some sort of "take at your own risk" issue or protection with over the counter, uncontrolled, nutritional supplements.
I'm not a lawyer but I am an American, just returning to Switzerland after a long trip to the US. I really don't think it matters what is written about potential side effects, someone could still go to court if harm was done. An example would be cigarettes, they have warnings yet the cigarette manufacturers are constantly being taken to court. Of course, if the product is known to be potentially harmful and no warnings are given it would be much worse for the manufacturer if it harmed some people.
There are absolutely no data suggesting creatine is not safe. Conversely, there is an enormous amount of data suggesting it is safe and may have therapeutic benefit for specific medical populations. There is more long-term safety data on creatine than any supplement that I know of (including carbohydrate). I think that there is a lot of hysteria about safety of supplements in general that overblows the possible dangers. The supposed rash of positive drug tests from "andro supplements" has added fuel to the fire. For example, I was in Italy last week at a meeting and in the Q&A someone warned about the "danger" of supplements for athletes. Then during the break, this same individual was puffing away on a cigarette (unfortunately like the majority of people at the meeting). Mark Tarnopolsky and I were simply amazed that this individual was so worried about safety of supplements and yet evidently ignored the known real health risks of smoking.
Anyone eating any food or taking any supplement or medication should be informed about what they are taking and potential risks. A standard "warning label" in my view is wholly unjustified when numerous studies have reported no adverse effects. Safety can simply be verified by requiring HPLC tests for purity and impurities, making sure the supplement company adheres to U.S. Pharmacopia standards for production, etc (see Plisk and Kreider, Strength and Conditioning, 1999). If there are scientifically determined risks, then the public should be notified. However, when no risks have been uncovered in numerous short and long-term trials, I think these types of statements add to the public confusion and are simply misinformation.
The legality issue is one similar to any health or medical advice given by professionals in our field. As long as practitioners follow scientifically based recommendations and have references supporting their recommendation, then they are following the standards of care and cannot be legally liable. If there is no evidence of any short- or long-term side effects directly attributable to creatine supplementation, then one cannot be held liable for recommending use. One could make a similar case of "risk" for things like driving cars, alcohol, or even exercise. If a company markets an unsafe supplement, then they should be liable if they learn that the supplement is not safe through research or a rash of complaints about a given supplement. A statement like this would neither properly educate the public nor protect the manufacturer.
My posting has generated about 10 valuable responses so far, thank you. At this stage I want to clarify a few points.
1. I wrote: "Manufacturers of creatine--and of any other ergogenic aid that has not been properly assessed for risks to health--should consider..." Instead of "properly" I should have written "exhaustively", at least in the case of creatine. My apologies to the creatine cartel. I am on your side, guys.
2. I am getting messages from people stating that there is absolutely no evidence that creatine has harmful side effects. Perhaps they could send me or the list a commentary on the 2-3 case reports of kidney damage associated with creatine use. I haven't looked at these reports yet. My excuse is Easter. I understand at least one of them was associated with a pre-existing kidney condition. They are cited in the letters to the editor in the January issue of Med Sci Sports. Are these cases the tip of an iceberg, or does that fact that there are so few cases demonstrate just how safe (but not absolutely safe) creatine is?
3. Suppose you do one of the best safety trials yet, involving a double-blind randomized trial of 10,000 athletes over 5 years, and suppose you find no harmful effect. Your study does not exclude the possibility that 1 athlete in 5000 could suffer harmful effects after 5 years of use, or that many more athletes could suffer harmful effects after 10 years of use. And if you think that's fanciful, look at the recent report that megadoses of vitamin C harden your arteries. (NewScientist, 11 March, p.21)
4. If it turns out that creatine or whatever is responsible for a serious health problem for one person in say 10,000, should those people be allowed to sue the company? Not in my concept of natural justice, provided everyone was warned beforehand. So I think the answer is to assess the risks on the basis of the available evidence, get the assessment peer reviewed, put it on the label, then let the buyer beware. It might harm sales initially, but the public would get used to it, especially when they have to buy cars with similar labels and discover that driving a car is a lot riskier than taking creatine. As new evidence comes in, you update the label. People could bring a case against you only if they had evidence that you had underrated the risk, either deliberately or carelessly.
I'm out of my office but when I return in the morning I will forward you a passage from our book that evaluates the renal stress argument (including those case studies). Since publication of the book, there have been a number of well-controlled studies evaluating whether creatine increases renal stress. None of the short or long-term studies have shown any evidence of increased renal stress. This includes studies of 9 months to 1 year. We are presenting data this summer showing no effect on renal stress up to 15 months of monitored intake compared to controls (creatinine clearance studies). In some of our retrospective studies, there was no difference in creatine users versus non-users in markers of renal stress for up to 3 years of supplementation. See some abstracts from our long-term safety study at:
A 1 in 1000 response does not establish a statistical relationship. If renal stress occurred in 1 in 1000 subjects, there is no way to know whether it was due to creatine, any other interaction, or is completely unrelated. We don't make medical or scientific judgments based on case studies or studies reporting 1 in 1000 rate of occurrence. A statistically significant pattern or relationship must be observed. While larger n-size studies may uncover some previously unknown problem, the probability of occurrence and statistical outcomes can be estimated based on lower n-size studies. In order to show increased renal stress, one has to establish that short or long-term supplementation significantly decreases renal function/creatinine clearance in a group of creatine users versus controls. So far, every study that has evaluated this potential relationship shows no significant effects when evaluating creatinine clearance or albumin clearance rates in short or long-term controlled studies.
Additionally, despite the wide spread use of creatine, there are only three reports of "possible" problems. In two of these case studies, they based their interpretation of increased renal stress because serum creatinine levels were 1.4 and 1.7. There was no other evidence supporting renal stress reported. These reports have been strongly criticized. Using these criteria, most of the athletes in my control group who don't even use creatine have "renal stress". Exercise increases creatinine levels in both serum and urine levels as it reflects muscle degradation of creatine. Are we going to ban exercise because creatinine levels or muscle and liver enzymes go up? Our recommendations must be based on scientific findings based on sound statistical analysis which provide our most educated way of assessing the potential safety or hazards of any training method or technique. Case studies can lead us to evaluate a "possible" relationship. Well-controlled clinical trials allow us investigate the validity of the case study. We should not be putting warning labels on training devices or supplements unless there is consistent and sound scientific data to support the warning. We certainly would not support putting labels on training devices or supplements that show improved performance or medical outcomes in 1 of 10 or 1 in 1000 users.
Here is the passage from our book. It includes available reports up to March 1999. Since then, several studies have been published showing no effects of creatine supplementation on renal function in studies lasting up to 15 months in duration. Retrospective studies in athletes and patients report no effects up to 5 years of supplementation. The Sipilla group has actually been monitoring their group of gyrate atrophy subjects for 17 years (described in chapter 9 of our book). My take on the renal question, based on all available data up to today, is that this potential side effect is overblown. The data that has been presented and published over the last year provides convincing evidence that there is no relationship.
"In summary, analysis of available literature indicates that acute and chronic creatine supplementation (up to 5 yr) does not appear to increase renal stress in healthy individuals. Additionally, no adverse effects of low-dose, long-term creatine supplementation (1.5 g/d for 1 to 5-yr) on renal function have been reported in clinical trials (Sipilš et al., 1981; Vannas-Sulonen et al., 1985). It should be noted, however, that few studies have comprehensively evaluated the effects of creatine on renal function. Consequently, additional research using more precise methods of assessing renal function (e.g., inulin clearance) is warranted before definitive conclusions can be drawn."
I am not an attorney but follow the courts with more than a casual interest. In the US, I do not think that any warning is foolproof protection. With the recent court decisions going in favor of tobacco users (even those who started using after the surgeon general's warning appeared on cigarette packages), I doubt that the warning you suggested would hold up. Of course, the disdain for the tobacco industry in the US probably exceeds that of the creatine manufacturers/distributors. Also, juries seem to think that companies with deep pockets can afford the money or that insurance will cover it so no one really loses any money.
I have asked my brother (who is an attorney and has sued large corporations successfully) about warnings and assumptions of risk, since I once put on a 5K road race. His advice was to put a warning on the application and then do my best not to do anything stupid. (Glad I did not pay him for that advice!).