[ed. note: Michael Jorrin, a longtime medical writer who has earned the nickname “Doc Gumshoe” despite his lack of a stethoscope and medical diploma, is our favorite scribe on all topics health related — we feature his columns every couple weeks here at Stock Gumshoe to help us bring some skepticism and plain speaking to non-investment topics. Michael’s subjects are of his choosing, and his words and opinions are his own]
Even the words “supplements” and “drugs” evoke mental associations that take us in contrary directions. A supplement is something added to supply a deficiency. A diet supplement implies that there’s a deficiency in the diet that is being met by adding another, non-dietary substance. If we don’t get enough calcium from our regular diet, drinking more milk is not a diet supplement, but taking a calcium pill is a diet supplement.
The word “drugs” is considerably more complicated. My indispensable Oxford English Dictionary says the ultimate origin is uncertain, and gives this definition (in part):
“An original, single, medicinal substance, organic or inorganic, whether used by itself in its natural condition or prepared by art, or as an ingredient in a medicine or medicament.” And also, “Now often applied, without qualification, to narcotics, opiates, hallucinogens, etc.”
My Webster’s International (Second Edition) says: “Any substance to be used in medicine for internal or external use.” But also, “Any commodity that lies on hand or is not salable; an article of slow sale or in no demand, as a drug on the market.”
So, from the start, there’s a semantic implication that a diet supplement is something we need that is missing from our regular food intake, whereas a drug might be helpful in dealing with a medical need, but might also be something bad. No wonder terms like “pharmaceuticals” or “medications” are preferred.
So, is it true that “drugs” are too often harmful, while “supplements” are natural substances that are only beneficial?
To the first part of that question, one can only say “yes,” because any incidence at all of harm due to drugs (medications, pharmaceuticals) is too often. But to the second part, that diet supplements are only beneficial the view from this corner is that while some may be beneficial, they are also, certainly, too often harmful.
There is a simple reason for this: there is no fundamental difference between the active ingredients in drugs and those in diet supplements. They are chemicals. They may be simple molecules, as simple as salt or sugar, or they may be large, complex molecules. But they are chemicals all the same, and any chemical that has the potential to affect our physiology in a beneficial way also has the potential to affect it in a harmful way.
The phrase in the OED definition cited above – “whether used by itself in its natural condition or prepared by art” – is specific and clear. Willow bark is a drug, and salicylates, which copy the active molecule in willow bark, are drugs. (Aspirin is a salicylate.) The extract of the Pacific yew, taxol, is a drug, as are all the valuable cancer drugs derived from it. We no longer make a tincture of willow bark to relieve pain and lower fever, and there are probably not enough Pacific yews on the planet to treat all the cancer patients that are benefiting from taxol-based drugs.
The list of drugs directly derived from nature would be exceedingly long, and it is being added to every day. I heard the biologist Edward O. Wilson say that in every shovelful of dirt in the Harvard Yard there is an organism of some kind from which a drug, valuable to humans, could be derived.
Why is this? We could point to survival as the driving force – not our survival as humans, but the survival of the plants and animals from which we derive drugs. Exenatide (Byetta, from Amylin Pharmaceuticals and AstraZeneca), a drug for type 2 diabetes, was based on the venom of the Gila monster, and a peptide found in the venom of the pit viper led to the development of the first ACE inhibitor. But we would not use Gila monster venom to treat diabetes, or pit viper venom to lower blood pressure (unless the objective was to lower it to zero!). Evolutionary forces resulted in the emergence of active agents in these animals that enabled them to compete in the world, and we can learn from nature to enhance our own survival. We do not use these drugs by themselves in their “natural condition.” We prepare them “by art.”
What about all those dangerous drug side effects?
Every advertisement for a drug includes a list of potential side effects. This is necessary and appropriate. It is an absolute FDA requirement that in any promotional material for a drug, the side effects have got to be stated. The way it works is that adverse events in patients treated with the drug that occurred with greater frequency than in patients treated with placebo are assumed to have been in some way caused by the drug. If we’re talking about the most frequent side effects, this is most likely true.
That assumption is based on statistics more than on a specific understanding of how the drug produces the side effects. And a similar statistical assumption is the basis for confidence in a drug’s efficacy. We don’t have to know the drug’s precise mechanism of action – all we really need to know is that people taking the drug attain a certain degree of benefit, and that people with the same disease condition and similar characteristics, but who are taking a placebo instead of the drug, do not attain that degree of benefit, so it must be that the drug is making the difference.
When it comes to the serious adverse events, including serious infections and malignancies (which is what most of us are concerned about) that statistical comparison may not apply. The problem here is that these serious adverse events tend to be quite infrequent, so the statistical standard doesn’t work. The numbers are just too small. All serious adverse events (SAEs) must be stated, whether or not they can be attributed to the drug. And this also is necessary and appropriate. Health professionals are assumed to be competent to understand the data and make an appropriate decision based on the balance between the risk and the benefit to the patient.
However, the data can certainly frighten patients. Here’s an example, from a project I recently worked on, involving juvenile idiopathic arthritis, which is a troubling disease affecting children as young as two years of age.
In a clinical trial involving 69 patients, lasting 6 years, there were 29 adverse events classified as serious. Of these, 10 were disease flares, meaning that at a certain point the disease was getting worse instead of better. There were 8 serious infections, a major concern since the drug being evaluated is an inhibitor of an immune response. Several of the SAEs may have been unrelated to the drug, e.g., appendicitis, a wound infection due to a knife cut to the patient’s hand, a wound infection following surgery for a chin implant, diabetes, dental abscess, a personality disorder. Two SAEs were likely to be related to the drug, e.g., herpes zoster and aseptic meningitis secondary to herpes zoster. However, whether drug-related or not, all the SAEs had to be reported, listed in the prescribing information, and the advertising has to reflect the prescribing information.
Naturally, this frightens a lot of people. And, in many cases, may dissuade people from agreeing to treatment courses that could be of benefit.
The crucial issue: balancing risk with benefit
At the extremes, this is not terribly complicated. At one extreme is when the drug is meant to address something relatively minor, but the risk associated with the drug is not minor at all. A perfect example is the discovery that some antihistamines (terfenadine, marketed as Seldane, and astemizole, as Hismanal) could lead to a dangerous cardiac arrhythmia known as torsades de pointes, if taken at too high doses or with other drugs that slowed the excretion of these antihistamines so that they built up in the system. Who would risk a heart problem that sometimes causes death in order to prevent sneezing or itching? In that case, it’s open and shut. (By the way, both of those drugs were taken off the market about 15 years ago.)
At the other extreme is the treatment of the factors that contribute to strokes or heart attacks in persons with demonstrated risk factors for those events. I am not talking here about the new proposed algorithm that was discussed at great length in a previous blog. I am talking about people who, for example, have already sustained a transient ischemic attack (TIA) or a heart attack, or who experience heart pain while at rest, or have established coronary artery disease. In patients such as those, the risk/benefit balance is unquestionably on the side of benefit. The evidence is strong that treating the conditions – hypertension, hyperlipidemia – that contribute to cardiac risk leads to very large benefits in terms of survival for such patients, while the risks are manageable.
For many people, the decision is not so easy. I have heard many rheumatologists say that in some cases direct-to-consumer advertising is a significant impediment to treatment, because the recital of all the possible side effects spooks their patients. The risk/benefit balance in such cases might need to be restated as a balance between two categories of risks: the risk associated with the drug, and the risk of untreated disease progression. In the case of rheumatoid arthritis, for example, the drug might present a relatively small risk of lymphoma or non-melanoma skin cancer, but disease progression can lead to disability and a significantly shortened life-span. Some patients might view the disease progression risks as distant, however, while the drug side effect risks are immediate and scary.
But don’t the drugs that are marketed as “supplements” also have side effects?
You bet they do. That’s because, as I said earlier, the active elements in supplements are chemicals, just as the active elements in drugs are chemicals. And if these chemicals, whether in supplements or drugs, have some kind of effect in our bodies, that effect can be for good, but also for ill – and not infrequently, both for good and ill.
Mostly, the adverse effects associated with supplements go under the radar, because they do not have to be stated in advertising, and there is no mandated prescribing information, as there is for FDA-regulated pharmaceuticals. But that doesn’t mean that they don’t occur and that in some cases they have serious consequences. Poison control centers in the US received more than one million reports of adverse reactions to vitamins, minerals, and dietary supplements between 1983 and 2004, resulting in more than 175,000 hospitalizations. And the FDA estimates that about 50,000 adverse reactions to supplements occur every year.
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An example that has recently received considerable notice is the unacceptably high incidence of liver injury, in some cases leading to liver transplantation, associated with diet aids consisting – supposedly – of a concentrated green tea extract. These adverse effects were tracked by a group established by the National Institutes of Health, which identified more than 800 patients with severe liver damage who required hospital treatment.
Several potential factors may be involved. One is that the active ingredients in the green tea extract are catechins. These are chemically related to some active neurotransmitters – dopamine, epinephrine, norepinephrine – and have been studied extensively. It has been suggested that catechins might have some efficacy in preventing cancers, such as prostate and breast cancer, and also in preventing metabolic syndrome; however, no positive evidence for these benefits has been found. On the “harms” side, catechins in high doses have been found to be toxic to the liver, and the green-tea based diet supplements are highly concentrated, containing a multiple of the amount of catechins contained in green tea.
Another potential factor is that these supplements contain other ingredients than green tea, sometimes including steroids, and in some cases, up to 30 different substances, none of which are listed on the label.
So, let’s see what the regulation of supplements might have to do with their safety…
What does supplement regulation amount to?
The FDA has seldom intervened in the marketing of drugs that were presented as “natural,” other than to place restrictions on medical claims unsupported by evidence. There were efforts by the FDA to regulate megavitamins; these were defeated in Congress in the mid-1970s. Then, in the early 1990s, there was another attempt by the FDA to regulate supplements, which was again defeated in Congress.
The FDA does, to a minor degree, regulate supplements, especially with regard to specific medical claims. A supplement cannot go beyond stating that taking that supplement “supports” a particular area of health, such as heart, bone, digestive, etc, unless – as happens very seldom indeed – there are acceptable clinical studies substantiating specific claims.
This restriction is easily circumvented. All the supplement marketer needs to do is find a compliant physician and a few patients who have used the supplement and experienced benefits, and the personal testimonials regarding the supplement’s effectiveness as a cure for any and all ailments can be propagated far and wide with no restrictions.
As for safety, the NIH language makes it clear that it’s the responsibility of the manufacturer to have evidence that the product is safe, but that they do not have to provide that evidence to the FDA before the product is marketed.
This does not amount to a whole lot.
But isn’t the FDA disposed against the supplements industry?
Now, there are those who will say that the FDA are stooges of Big Pharma and conspire to keep the supplements marketers in a subservient position so that Big Pharma can continue to rake in the profits.
To this, I say, “Not so!” The FDA and Big Pharma, as well as Not So Big Pharma, are frequently at odds, not to say at swords’ points. The FDA’s requirements for painstaking, slow, expensive evidence gathering is exceedingly costly and delays the ability of the drug’s developers to bring a drug to market for many years after the drug has first been identified as a potentially useful agent. Frequently, the FDA finds that the evidence submitted on behalf of a drug is insufficient and requires further clinical trials, or declines to approve the drug at all. My own view, as a skeptical observer, is that pharmaceutical outfits are enormously benefited by operating in a regulated environment, but that doesn’t mean that they’re not frequently locked in serious conflict with the FDA.
A black eye for supplements marketers
A recent Canadian study (Newmaster SG et al. BMC Med. 2013; 11: 222) reported that a majority of herbal supplements tested by DNA bar-coding were not as described on the labels. The investigators bought 44 samples of supplements from 12 different manufacturers / marketers, and compared their DNA bar codes with those of the herbs of which they purportedly consisted. The products of only two of the twelve marketers were exactly as described on the label. Two of the twelve contained no authentic ingredients at all – they were 100% fake. The other eight consisted of a mixture of fake ingredients, contaminants, and varying proportions of the labelled herb, sometimes as much as 50%, and sometimes considerably less.
The totally fake ingredients were mostly harmless, including rice, soy, and wheat. The contaminants were another story. One bottle was fraudulently labelled as St John’s wort, which is promoted as an antidepressant (it has been touted as a monoamine oxidase inhibitor; however, this mechanism is disputed). It was found to consist entirely of Alexandrian senna, which is a powerful laxative. Ginko biloba supplements were contaminated with black walnut, which might be fatal for people with nut allergies.
It is not necessarily the case that all ten marketers whose supplements were not as stated on the label are guilty of intentional fraud. Contamination may have occurred by error, during the harvesting of the herbal products. However, there doesn’t appear to be much excuse for the two marketers whose products contained no genuine ingredients at all, but only cheap fillers.
The Canadian study, by the way, did not identify the marketers of these supplements by name.
So, where does Doc Gumshoe stand on this issue?
My view is that the point of departure for a great many effective medical interventions is a naturally-occurring substance – an herb, a plant, a fungus – that is found to have healing powers. Necessarily, the first inkling of the effectiveness of these naturally-occurring drugs is anecdotal. Yes, anecdotal evidence is frequently dismissed – until it is verified through the strength of numbers, and until the mechanism through which these naturally-occurring drugs do their work becomes understood.
Dr Jerome Groopman of the Harvard Medical School recounts an interesting discovery of this sort. Healers in the Harbin region in Northern China used certain powders derived from rocks, and supposedly achieved “miraculous” cures of a form of leukemia called acute promyelocytic leukemia. The powders were found to contain arsenic trioxide, which is undoubtedly poisonous. But researchers at the Shanghai Institute of Hematology followed up the stories of cures and determined that indeed arsenic trioxide was the agent that led to these cures. There were rigorous clinical trials, and arsenic trioxide was recently approved by the FDA for the treatment of that form of leukemia, which is frequently fatal in a very short time. Arsenic trioxide changes the course of the disease, so that, instead of being fatal, it is frequently curable. The Shanghai researchers have now elucidated the specific mechanism of action of arsenic trioxide. It blocks a protein that triggers the growth of that leukemia.
That little story illustrates the progression from the anecdotal evidence to scientific verification. That’s how the feud between the proponents of supplements and those who dismiss supplements as quackery can be settled: verify – or disprove – the anecdotal evidence through rigorous scientific examination including clinical trials. Bring to bear the resources of science and the strength of statistics. Let’s bring the two sides together in the common quest for improved health.
News Flash! The New York Times Catches Up with Doc Gumshoe!
The Sunday Review on January 5th had a front-page story with this title and subhead: “Why Everyone Seems to Have Cancer: As heart disease and stroke are beaten back, cancer vies to become the final killer.” The writer, George Johnson, citing those mortality rates, comes to the grim conclusion that “if the heart holds out, then waiting at the end will be cancer.”
Some of you may recall my piece about cancer last June. It was called “What’s Happening in Cancer Treatment? Are We Making Progress, or Are We Stuck?” Here’s what I said in that one:
More Heart Disease Survivors Means More Cancer Fatalities
Cancer mortality rates are down, but not that much. One reason is a sort of statistical artifact: death rates from the chief killer, cardiovascular disease (CVD), are down sharply. According to the NIH, yearly heart disease mortality declined from 307.4 per 100,000 population in 1950 to 134.6 per 100,000 in 1999, and it has continued to decline steeply since then. For example, in my home state of Connecticut, mortality from heart attacks was 66.6 per 100,000 in 1999 and 41.5 in 2006. The American Heart Association calculates that if the CVD mortality rate had remained at its 1963 peak, 621,000 additional CVD deaths would have taken place annually from about 1996 onward – that’s almost 10 million people. But those folks who escape dying of heart attacks don’t live forever – lots of them survive to succumb to something else, frequently the big C.
Of course, it might be something else, the secret of immortality not yet having been discovered. But if the statistics, in fifty years or so, show that more centenarians are perishing while attempting to scale Mount Everest, we shouldn’t conclude that Everest has become more dangerous.
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Please keep the comments coming! Pat Doc Gumshoe on the back when you agree with him and rap him across the knuckles when you don’t! Right now, I’m gathering material for a piece about migraines, which seriously affect lots of people and have a major impact on their daily lives. Look for it in a couple of weeks. Best to all in the New Year, Michael Jorrin (aka Doc Gumshoe).