In short the foundation was an excellent example of why political ideology should not interfere with the normal process of science. The website for the charity no longer exists, but this is what it said about it’s mission:

“The Prince’s Foundation for Integrated Health is a UK charity championing an integrated approach to health.

“The Foundation works towards a culture of health and wellbeing with people and communities taking more responsibility for their own health, and where health professionals collaborate and share learning in the best interests of their patients.

“Integrated health means an approach to health which:

• “emphasises prevention and self-care
• “looks at the person in the round, taking into account the effects on health of lifestyle, environment and emotional wellbeing
• “brings together the safest and most effective aspects of mainstream medical science and complementary healthcare.”

This is typical CAM bait and switch. Preventive medicine, healthy lifestyles, and taking a complete approach to health is not alternative or complementary – it is part of mainstream science-based medicine. All of that is actually a misdirection from the real goal of the CAM or “integrative” movement – to promote health products and services that fail to meet minimal standards of evidence and plausibility, or which have already been shown to be ineffective. The Prince’s Foundation was not exception, promoting over the years every form of quackery from homeopathy to Reiki.

Perhaps the best criticism of the foundation came from Edzard Ernst who wrote:

He seems to think that the nation should be force-fed on alternative medicine today, while research into these treatments might be conducted some time in the future. I, on the other hand, have often pointed out that research has to come first; it should sort out the wheat from the chaff and, subsequently, we might consider integrating those treatments that demonstrably generate more good than harm. I therefore think that the FIH has become a lobby group for unproven and disproven treatments populated by sycophants.

Of course – integrating therapies proven by science is called science-based medicine. Edzard correctly points out that the purpose of the CAM category is to put practice before evidence, and even to go against the evidence, or redefine what should pass for evidence in medicine.

There was some speculation about what the company might do in the wake of the Foundation’s closing, but that has now ended with the demise of the company that funded the charity. When the Foundation closed in 2010 it was amid an embezzlement scandal. Although the Foundation claimed it was planning on closing because it had achieved it objective, and just sped up the timetable because of the allegations. But now those allegations have killed the sponsoring company. The Mail online reports:

The revelation led to the foundation’s finance director George Gray, 50, being jailed for three years for embezzling the sum over two years.

Southwark Crown Court heard how Gray regularly transferred up to £5,000 a time from the charity into his bank account to cover payments on his £700,000 mortgage.

It is heartening to see an organization dedicated to anti-science in medicine go under, but it is a shame that it took an unrelated scandal to do it. It would have been better if the Foundation closed because people finally came to their senses.

In the US we have our own versions of the Prince’s Foundation, namely the National Center for Complementary and Alternative Medicine (NCCAM) and the Dietary Supplement Health and Education Act of 1994 (DSHEA). The NCCAM is a vanity project of its major sponsor, Senator Tom Harkin, as much as the Prince’s Foundation was a project of Prince Charles. Likewise DSHEA was the result of the personal ideology of two senators, Harkin and Orin Hatch. The misnamed DSHEA essentially deregulated the supplement industry, leading to an explosion of dubious products, an expansion of the multi-billion dollar supplement industry, and all without a bit of evidence that there has been any benefit to the health of Americans. In fact, it is possible (and I think it’s likely) that there has been net harm.

It is unfortunate that a few politically powerful individuals can have such a disproportionate influence on an issue as important as health care. It is also generally not a good thing when politics or ideology are used to trump science – and that, at its core, is what CAM is.

It’s called RISUG: Reversible Inhibition of Sperm Under Guidance. It involves a minor surgical procedure in which the vas deferens is exposed and pulled outside the scrotum by the same techniques used for a vasectomy. A copolymer, powdered styrene maleic anhydride (SMA, for which the method was previously named) combined with dimethyl sulfoxide (DMSO) is then injected into the vas deferens. The polymer coats the walls of the vas and kills the sperm as they swim by. The mechanism is not understood, but the developer thinks the polymer’s mosaic of positive and negative charges causes the membranes of the sperm to burst, rendering them immotile.

RISUG is rapidly effective: in a phase II clinical trial in India, viable sperm were absent as soon as 5 days after the procedure. They say there have been no pregnancies in the first months “other than a handful of cases in which the RISUG was not injected properly.” (One wonders how they determined that it was not injected properly: by the fact that pregnancy occurred? Could this be just a rationale to explain away failures? Or to spare patients the embarrassment of discovering the wife had another sperm donor?) The contraceptive effect is said to last for a decade or more; it might require repeat injections every 10 years.

In contrast to vasectomy, RISUG can be reversed by injecting DMSO or bicarbonate and using a combination of vibration, a low electric current, and rectal massage to dislodge the polymer and move it through the vas deferens.

It is not yet approved in India, but it has already been patented in several countries. Efforts are underway to seek FDA approval in the US under the name Vasalgel, but don’t look for it on the market anytime soon: preliminary studies on rabbits are just getting started. 

It sounds crazy, but there is evidence to support it. A search for RISUG on PubMed brings up 18 articles. Some are lab studies, some are not directly relevant, and some are reviews of contraceptive methods; but there are a couple of very encouraging studies in monkeys and a report of a phase II human trial with 12 subjects. 

An article in Wired calls it the revolutionary new birth control method for men and includes a video so you can watch the actual procedure. It says:

It’s the brainchild of a maverick Indian scientist named Sujoy Guha, who has spent more than 30 years refining the idea while battling bureaucrats in his own country and skeptics worldwide. He has prevailed because, in study after study, RISUG has been proven to work 100 percent of the time. Among the hundreds of men who have been successfully injected with the compound so far in clinical trials, there has not been a single failure or serious adverse reaction. The procedure is now in late Phase III clinical trials in India, which means approval in that country could come in as little as two years.

There are some worrisome red flags here: lone genius, battling the establishment, reference to “study after study” when Phase III trial results are still pending, and the claim that it is 100 percent effective. No contraceptive measure is 100 percent effective, not even hysterectomy: abdominal pregnancy can occur even after a total abdominal hysterectomy.

Conclusion

RISUG may be a promising means of birth control for males, but it’s too early to draw any conclusions. The current media hype is unwarranted. Science will have to run its course and complete well-designed clinical trials before the method can be recommended.

I know, I know. My saying that is probably akin to saying that the sun rises in the east, water is wet, and Donald Trump’s hair resembles nothing in nature. You know, brain-meltingly obvious statements. It’s true, though. I despise cancer quacks. It doesn’t much matter to me whether the quack is a true believer or a calculating con artist, the end result is the same: People with cancer throwing their one best chance to survive away chasing pixie dust and promises of “natural” cures without the toxicity that is the unfortunate byproduct of the surgery, radiation, and chemotherapy that are the mainstays of our current armamentarium against cancer. I’m a cancer surgeon. This I cannot abide, which is part of the reason I became active promoting science-based medicine, started my other blog, and then was so eager to join up when the opportunity to join this blog presented itself four years ago.

It’s hard to blame patients, too. After all, as I’ve described so many times before, curing cancer is hard. Very hard. Cancer is complicated. Incredibly complicated. Quacks make it sound easy and simple. They postulate One True Cause of Cancer, and, as a result, often what they represent as the One True Cure for All Cancer. Faced with a life-threatening disease and the possibility of chemotherapy, surgery, and/or radiation therapy, patients are understandably frightened and, if they don’t have a scientific background, susceptible to the blandishments of quacks. That’s what happened to a patient I wrote about long ago, and that’s what happened to Kim Tinkham.

It’s also what is happening right now to a woman named Danielle, and, worse, she’s falling victim to the same cancer quack. Worse still, from my point of view, she’s blogging it.

I came across Danielle’s blog because I happen to have a Google Alert for this particular cancer quack, and last week up popped a blog called New Life – A New Beginning. I knew it was going to be a problem when I saw the most recent post Good News!, which featured a credulous video promoting the Gerson Therapy. You might recall that the Gerson therapy was the basis of a movie called The Beautiful Truth that I reviewed a couple of years ago. At first I was going to ignore the blog, given that I’ve written about Gerson, and I would have had to watch several videos if I wanted to write about the most recent post on the blog, but something—curiosity, I don’t know what—compelled me to go to the beginning and read, and what I found was both frightening and, conveniently enough for purposes of this blog, a a perfect introduction to a particularly prevalent form of cancer quackery. Since the blog has only been in existence since January and much of what was posted thus far has been brief, including inspirational poems and prayers, it didn’t take me long to locate the key posts that discuss what Danielle, with the support of her husband Brad, has chosen in lieu of conventional therapy.

The diagnosis and the prognosis

In January, Danielle was diagnosed with breast cancer. In the U.S., this is all too frequent an occurrence, something that happens approximately 226,000 women every year, with close to 40,000 deaths. Danielle is from Canada (note the .ca in her blog and her mentions of going to the Cross Cancer Institute, which is in Edmonton. Ultimately, she decided to travel to southern California, but that’s getting ahead of the story. Let’s first just take a look at Danielle’s own description of her diagnosis in a post she calls (and I give her credit for cleverness here) more infearmation:

Today we met with our oncologist. The cancer is now considered Stage 3. They have not yet completed all the tests to see if it has attached to any other organs, which, if it has, would bring it to it’s final stage of 4.
From the MRI results, there is a very large tumor with a large blood vessel feeding into it, along with a couple more tumors in my breast. Many lymph nodes are also full of cancer.

This is an aggressive, fast growing cancer, not run by hormones like most breast cancers are, but by a protein called HER2.

I will begin chemo treatments next week, on Thursday, the 2nd.

If all is clear in the rest of my body, the chemo will go on for 4 1/2 months and then my breast will be removed as well as many, if not all of the lymph nodes on that side. After surgery, I will undergo a month of radiation, five days a week. THEN, they are proposing putting me back on chemotherapy.

I tried to absorb all of the potential side effects that this chemo treatment will bring. I think I’ve gone numb.

As Chloe says every night, “I want my normal life back.”

Yes, I’ve heard this lament all too many times. Cancer patients do want their normal lives back, and that’s completely understandable. Before cancer, they could plan on living into their 70s, 80s, or even 90s; after cancer, it’s not clear that they’ll live even a couple of more years. Their lives have to be put on hold while they endure toxic and invasive treatments that might not even save their lives.

There’s no doubt, either, that Danielle has a nasty tumor. However, it is far from a hopeless situation. As she announced in a later post, there was no evidence on CT scans or bone scans that she had distant metastases (i.e., tumor that’s spread beyond the regional lymph nodes). However, as her husband Brad also characterized Danielle’s disease in a later post, she had stage IIIC disease, which tells me that she either has at least 10 axillary lymph nodes with cancer in them, tumor in the supraclavicular lymph nodes, or tumor in the internal mammary lymph node chain (just near the sternum). Because it’s not possible to know how many lymph nodes have cancer in them without removing them all to look, I presume that this means that Danielle has at least one enlarged supraclavicular node that was biopsied and found to have tumor, which is the most common reason for being staged at IIIC. However, she has no detectable metastases in organs like the lung, liver, bone, or brain. What that means is that Danielle is still potentially “curable” (oncologists don’t like to use that word, but it does convey the possibility of long-term survival and living out the rest of one’s natural life expectancy free from breast cancer), but just barely. In essence, she has cancer that is at the limits of modern science-based medicine to eliminate.

Moreover, it’s certainly true that a tumor that is estrogen receptor (ER) and progesterone receptor (PR) negative tends to have a worse prognosis than and ER/PR-postive tumor. However, in a perverse way, the fact that the tumor is HER2-positive is a good thing. It didn’t used to be. Back before Herceptin, HER2 positivity was viewed as a poor prognostic sign because it portended a more aggressive, less differentiated tumor. However, post-Herceptin, these patients do considerably better because of the efficacy of Herceptin at targeting the HER2 oncogene and shutting it down. We’re now developing other drugs to do the same thing because Herceptin, being a humanized monoclonal antibody against HER2, has to be given intravenously, while newer drugs such as lapatinib can be taken orally.

It also sounds to me as though the oncologists were recommending the appropriate therapy: Neoadjuvant chemotherapy (chemotherapy before surgery) to shrink the tumor, followed by surgery to remove residual tumor, followed by radiation therapy, and then a year of Herceptin (trastuzumab), a targeted therapy against the HER2 oncogene. As brutal as this regimen sounds, knowing what I know in general about patients with stage IIIC breast HER2-positive breast cancer, I can say with some confidence that her situation, although dire, is far from hopeless if she were to undergo the standard-of-care therapy recommended by her oncologists and surgeons. In fact, she might have as good as about a 50-50 chance of surviving five years and a slightly lower chance of surviving 10 years, although her chances are probably less than that. While these are not the greatest odds in the world, they are better than for a lot of cancers, and she can survive this thing. One thing that you need to know about ER-negative breast cancer, it’s that, unlike the case of ER-positive tumors, which, although they have a better overall prognosis than ER-negative tumors, have a nasty tendency to recur later than five—or even ten—years, for ER-negative tumors five year survival is actually a pretty good surrogate for long-term survival. The reason is that for ER-negative tumors late recurrence is a lot more uncommon. ER-negative tumors (particularly the so-called “triple negative” tumors, which have neither ER, PR, nor HER2), tend to recur early, within three years, if they’re going to recur at all, and the vast majority of deaths from triple-negative and ER-negative disease tend to occur before five years.

Just to give you an idea, I refer you to this table from the American Cancer Society, and then to two graphs. Data from the table are from patients diagnosed in 2001 and 2002. As you can see, the estimated survival for patients with stage IIIC cancer is 49%.

This agrees with graphs I generated by using Adjuvant Online. For those of you not familiar with Adjuvant Online, it’s a website that uses data from the medical literature to provide estimates of expected outcomes for various treatments of different cancers. It’s unfortunate that it doesn’t include HER2 status and the results of Herceptin therapy yet. AO is, unfortunately, a few years behind the times because in the estimation of its authors the long term data for Herceptin is not yet mature enough to incorporate into their models. No doubt that will be remedied in the future edition being worked on now. However, we can approximate Danielle’s case by combining facts (that her cancer is ER-negative) with some educated guesses (such as her age, which appears to be fairly young) and assuming that the tumor has the worst characteristics possible. So I assumed that Danielle is 40 years old, listed her tumor as ER-negative, and chose the worst grade for it. I then made some reasonable guesses about potential characteristics and produced a few graphs, which I’ve arranged from worst to best. I did this because I don’t know enough about Danielle’s situation to be more precise:

As you can see, the estimates of Danielle’s prognosis range from, at worst, around a 30% chance of surviving 10 years to nearly 50%. Because Danielle’s cancer is HER2-positive and could benefit from Herceptin, I’d tend not to be as pessimistic as the lowest estimate and place her chance of surviving 10 years somewhere between 40-50%. As I said before, these odds are anything but great. They are, for example, very different from the 90%-plus chance women with stage I breast cancer have of surviving their disease. But they are far from hopeless. More importantly, look at the green part of the graphs. They represent the chance of surviving ten years with surgery alone. The odds of surviving ten years with surgery alone ranges from 5% to around 19%. Without surgery, it’s virtually zero, and her chance of living even five years without treatment is quite low. And, make no mistake about it, no treatment is exactly what Danielle has chosen.

So why would a relatively young woman with everything to live for choose something that has no chance of saving her life over something that has perhaps a 40% chance of saving her life? Let’s find out.

Enter the quack

Somewhere, somehow, somewhen, Danielle, as is the case for so many breast cancer patients, went on the Internet. While the Internet can be a fantastic resource for information on cancer, it is also, unfortunately, also a fantastic resource for quacks to use to spread slick, seemingly reasonable propaganda for their pseudoscience for very little expense. For instance, on February 5, Danielle was very enamored of an article by someone named Gregory Delaney that’s been floating around the Internet entitled Curing Cancer with Baking Soda: What MD’s and Naturopaths Don’t Know. The article, as you can tell from its title, is a load of pseudoscience, indicating a complete lack of understanding of cancer. Delaney also rants against oncologists as “disciples of fraud” and claiming that the cancer is not the disease, but rather a manifestation of…something else. Instead of embracing the claim that cancer is a manifestation of buried emotional trauma (as do the German New Medicine and Biologie Totale), Delaney embraces the claim that cancer is not a disease but rather a “reaction of cells to various factors that will cause their death if they do not devolve to a lower, cancerous state.” His solution? Just what the title says: Cure cancer with baking soda!

Given that foreshadowing, it’s sadly unsurprising that, in Danielle’s case, the Internet apparently ultimately led her to one “Dr.” Robert O. Young. We’ve met Young before doing what he’s doing here, leading a woman named Kim Tinkham away from effective treatment and, in essence, to her ultimate death, but I’ve never discussed his beliefs other than briefly. I mean to remedy that situation now. Basically Young believes in “alkalinization” über alles as a cure for not just cancer but all disease, and that’s why he calls his variety of cancer quackery “pH Miracle Living.” Young even goes so far as to label his “understanding” of cancer as the “new biology,” which sounds way too much like the German New Medicine and Biologie Totale. But first, let’s hear about Danielle’s decision from her own keyboard:

Today I told the Doctors that I will not be using conventional methods to treat this, at this time.

I know it has been effective in saving so many lives, but this was MY decision.
Given that I was told, due to the aggressive nature of this particular cancer, that these treatments may or may not cure this, they may only extend my life by a few months, the cancer may return, I would most likely suffer heart damage, the irreversible shut down of my hormones, the destruction of my immune system, the loss of my lymph nodes, my energy, my breasts (would likely remove the other as precautionary), my hair temporarily, and the list went on and on… I would head into surgery with no immune system and then when I’d recovered from that blow to my body, I would undergo rounds and rounds of radiation, and while healing from the trauma of that I would be put back on chemo therapy and my immune system again would be destroyed, and if I ever got sick while on these treatments it would be a life or death emergency.

We have discovered extensive, empirically founded research and proven results with many alternative treatments for cancer. There are no guarantees either way, so all I have is the information I have been given, the life I have been given, and the choice of how I live it, for me and for my family.

I am working with a microbiologist Doctor, whose knowledge and practice has resulted in phenomenal outcomes, to implement an intense protocol that will heal my blood.

I’m simplifying things quite a lot here. I realize this won’t make sense to many of you, but for me, this makes the MOST sense; at least, to have this treatment be my FIRST line of defense.

We will receive regular tests and monitor my progress.

I’d hate to be Danielle’s oncologist. What a moral dilemma he must have! As a doctor, you don’t want to abandon a patient, but on the other hand you can’t support this sort of pseudoscience.

Yes, this “microbiologist Doctor” whose practice has allegedly “resulted in phenomenal outcomes” is “Dr.” Robert O. Young. Young bills his treatments as “pH Miracle Living” and even goes so far as to label his “understanding” of cancer as the “new biology.” His “new biology,” however, is nothing more than a mish-mash of old quackery involving live blood cell analysis with his own special (and not so original) spin on “alkalinizing” the blood. For instance, here is what YOung thinks to be the cause of cancer:

Cancerous tissue, above all other consequences of choice, has countless secondary causes. But even for a cancerous condition there is only ONE PRIME ORIGIN and CAUSE. I have simply summarized this origin and cause of cancerous tissue in a few words. The prime origin and cause of cancerous tissue is the over-acidification of the tissues then the blood due to lifestyle and dietary choices. A cancerous tissue begins with our choices of what we eat, what we drink, what we think and how we live. Cancer is a liquid and this liquid is a toxic acidic waste product of metabolism or energy consumption.

All of which is so wrong that it’s not even wrong. But there’s more:

The following is a summary of understanding cancerous tissues:

Cancer is not a cell but a poisonous acidic liquid.

A cancer cell, is a cell that has been spoiled or poisoned by metabolic or gastrointestinal acids.

A tumor is the body’s protective mechanism to encapsulate spoiled or poisoned cells from excess acid that has not been properly eliminated through urination, perspiration, defecation or respiration.

The tumor is the body’s solution to protect healthy cells and tissues.

Cancer is a systemic acidic condition that settles at the weakest parts of the body – not a localized problem that metastases.

Metastases is localized acids spoiling other cells much like a rotten apple spoiling a bushel of healthy apples.

There is no such thing as a cancer cell. A cancer cell was once a healthy cell that has been spoiled by acid.

The tumor is not the problem but the solution to protect healthy cells and tissues from being spoiled from other rotting cells and tissues.

The only solution to the acidic liquids that poison body cells causing the effects that medical savants call cancer is to alkalize and energize the body.

In conclusion, the human body is alkaline by design and acidic by function! If we desire a healthy body we must maintain that alkaline design.

When I pointed out the similarity between the German New Medicine and Robert Young’s quackery, I wasn’t kidding. Both view the tumor as not being the actual disease but rather a “reaction” to something else. In the case of the German New Medicine, the tumor is supposedly a reaction to past emotional traumas; in the case of Young’s beliefs, it’s a reaction to “overacidification” of the tissues. To fight this “overacidification,” Young recommends a whole host of treatments, mostly dietary, and claims that they will cure cancer.

We get an idea of what this involves just by looking at some of of Danielle’s posts. First, let’s look at what Young told Danielle, as reported by her. The causes of Danielle’s breast cancer include, according to Young, rarely drinking water, not eating consistently, eating big meals, eating sugar, not taking deep breaths, being indoors too much, being under stress, being impatient and judgmental, not getting enough sleep, having a “clogged up digestive system” (remember the “toxins” and colon flushes), having blood “full of yeast,” and, of course, being exposed to all sorts of “toxins.” It’s a veritable cornucopia of nonsensical ideas about human physiology that have little or no (with an emphasis on “no”) grounding in science. In fact, one wonders how Young can keep all these causes straight and how he relates them all to “overacidification” of the blood, because apparently, according to him, virtually anything can cause overacidification of the blood.

If you look more closely at Young’s writings, it’s not hard to find that there is almost no form of quackery that he does not embrace. For instance, he is a germ theory denialist:

One must challenge everything in the modern construct of immunology and what is said to be the immune system. The basis of modern immunology is founded on Louis Pasteur, the fraud, impostor, deceiver and self promoter. There is a serious problem to where every word and part of the anatomy must be questioned to find their use and function because of the fraud of Louis Pasteur.

If you really want to see how far he’s willing to take it, look at Young’s explanation of what antibodies are. Not for Young is the standard explanation that antibodies are part of the immune system that bind to specific antigens and assist in the neutralization and elimination of invading microorganisms. Oh, no! Young knows what antibodies really are:

My final example is in defining the truth about antibodies and antigens. Antibodies are chemical clusters or alkaline buffers to a typical acidic condition properly referred to as antigens or enzymes. So called antibodies are released from healthy organ cells, such as the liver, in response to buffer and neutralize the acidity or liquid acid antigen that was first introduced. It must be noted that the word, antibody and antigen, are a Pasteurian dogma construct. The mind set being that an antibody or now even antibiotics, are defending or responding to bodies, microbes or invisible bodies or what I call phantom viruses, like Avian, SARS, or even HIV — even though HIV is not a virus but an alkaline antibody to buffer acid or antigens. The chemical response is actually due to an introduction, vector or antigen of a chemical nature, typically acidic, not a body, microbe or bacteria or yeast.

The above statement reveals such a fundamental misunderstanding of the biology of the immune system—indeed of biochemistry, given that Young apparently thinks that antigens are not really proteins and has no clue what their function is—that it boggles the mind. To him, the known function of antibodies is nothing but “Pasteurian dogma” (never mind that antibodies weren’t discovered until long after Pasteur’s discoveries), and their real function is to buffer acids with alkali, an idea that would certainly come as news to immunologists, biochemists, and physicians. Indeed, so much of a germ theory denialist is Young that when a young Brazilian model tragically died of bacterial sepsis, he blamed it on acid:

Ms. Bridi da Costa, at the young age of 20 died from systemic acidosis from the lack of proper alkaline treatment. Acidic drugs, such as antibiotics and metabolic acids ravaged her body which forced doctors to perform amputations of her extremities and extract part of her stomach as well as both kidneys. I strongly believe that Ms. Bridi da Costa would be alive, healthy and strong today, if, the prevailing 19th Century germ theory medical dogma and subsequent acidic treatment protocols of antibiotics would have been simply replaced with alkaline fluids of sodium, magnesium and potassium bicarbonate and alkaline water and foods.

And:

Body cells transform or breakdown to bacteria and yeast and then to mold as a result of excess tissue acidity and not from an infection from the atmosphere. Therefore, Germs DO NOT CAUSE DISEASE but are the result of excess tissue acidity not eliminated through urination, perspiration, respiration and/or defecation! Acid is the only CAUSE of dis-ease and disease, including sepsis!

Also, apparently viruses are not the cause of disease, but rather “molecular acids.”

I should have remembered: Young is a follower of Antoine Béchamp. He’s a germ theory denialist. Béchamp, as you may remember, was a contemporary of Louis Pasteur and proposed a competing hypothesis for the cause of infectious disease, which he dubbed the pleomorphic theory. The concept he championed was that bacteria do not cause disease but are rather a manifestation of disease. In other words, diseased tissues produce bacteria, arising from structures that Béchamp called microzymas, which to him referred to a class of enzyme. Béchamp postulated that microzymas are normally present in tissues and that their effects depended upon the cellular terrain. Of course, as we all know, ultimately Pasteur’s ideas won out based on evidence, experimentation, and clinical observation, relegating Béchamp to more or less a historical footnote. In fairness, it should be remembered that, 150 year ago, it wasn’t entirely clear who was correct, Pasteur or Béchamp. Given the technology and tools of the time, it was not a trivial matter to determine where bacteria arose, although it didn’t take long before experiments and methodology were developed that pretty much put Béchamp’s concepts to bed for good.

Except for people like Robert O. Young. His ideas incorporate Béchamp’s 150 year old ideas

I could go on and on and on. Truly, as Stephen Barrett put it, there’s so much pseudoscience and misinformation in Robert Young’s books and beliefs that it would easily take a book to refute them all. In the meantime, I thought it would be worthwhile to take a look at just what following Young’s regimen to treat cancer entails. Danielle, it turns out, provides the details in a post she entitles A Day in the LIFE. Truly, it’s a daunting list of “treatments,” including drinking mineral salts, drinking one liter of alkaline water, taking a “pile of supplements” (Danielle’s words, not mine), drinking another liter of water with chlorophyll and concentrated green vegie powder (what are we, plants, that we need chlorophyll?), eating a liquid meal, doing a colonic, drinking another liter of green water, checking her body’s pH, taking some more supplements, drinking a fourth liter of water, having another liquid meal, drinking a fifth liter, taking some more supplements, drinking a sixth liter of green water, sitting in an infrared sauna, taking a salt bath, dry brushing her skin, and—of course!—taking more supplements.

Wow. And Young complains that conventional medicine takes a lot of effort.

There is no science behind Young’s beliefs. He combines germ theory denialism, vitalism, and a complete misunderstanding of acid-base physiology into a toxic brew with which he entices his marks. Contrary to what patients like Danielle are told, there is no large, robust body of research supporting his approach. There is no evidence that what he does makes any difference whatsoever, while there is copious evidence that foregoing effective treatment greatly increases a cancer patient’s risk of death.

Why do cancer patients fall for this?

It’s not that difficult to understand why Robert O. Young’s message is so seductive to cancer patients. He offers hope where conventional oncologists and surgeons are ethically and professionally obligated to offer their best assessment of the patient’s prognosis and what results they can expect with science-based therapy. Quacks like Dr. Young are not constrained by the truth. It works, too, unfortunately. If you don’t believe me, look at this post by Brad, Danielle’s husband, in which he answers the criticisms of an anonymous commenter who had the temerity to point out that Dr. Young has no scientific credibility. Perhaps the most telling passage from that post is this:

We discovered that the prognosis for this type of cancer was pretty grim, no wonder the “Dr’s” were so tight lipped about the efficacy of their treatments. When talking with them, we received NO sense of reassurance, or confidence that their treatments would work to remove the cancer; they were confident about removing the tumor though (not to mention her breast and the majority of her lymph nodes on her left side). “But wait a second, what?!” – we assumed chemo, surgery, and radiation were a sure thing. No? Well… the research shows that, on average, a person lives 3-4 months longer when these treatments are used (if you’re able to survive the treatments of course). Three to four months longer, that’s statistically significant according to the research because she’s only expected to live 23 months without it, so 26-27 months is significant, statistically speaking – (“who cares about quality of life for the remaining MONTHS of your life, right?”).

What the doctors were CERTAIN about were the side effects. In fact, we heard about 3 hours worth of side-effects related to their proposed treatments. They said, “so, the cancer may grow resistant to the treatments we bombard it with. We can pretty much guarantee heart damage, with a side of intestinal destruction, and we know we can absolutely destroy your immune system and anything else your body could use to heal. And to top it off, you get to lose your hair, have no energy and walk around like a zombie. Don’t worry, as soon as you feel better we’ll make you feel terrible again… how about it?!” I was quite unimpressed when I knew more than the “oncologist” did (thank-you research) about the functional mechanisms of one of the drugs she was proposing to use. Ummm… awkward!

Somehow, if Brad’s posts are any indication, I doubt that he understood the functional mechanism of drugs better than the oncologists, particularly if he was repeating the same sort of misinformation and misunderstanding that Robert O. Young promotes. I’m also a bit confused. The discussion that Brad relates sounds very much as though the oncologists were assuming at the time that Danielle’s cancer was metastastic. When we as oncologic surgeons and oncologists discuss treatment options with potentially curable patients, we do not usually speak of median survival times. Far more often, we tend to talk about the odds of producing a five- or ten-year survival. In other words, we talk in terms of what the odds of a cure are with various treatment options. We usually don’t switch to “median survival discussion mode” until after it has become clear that long term survival is no longer possible, as in the case of stage IV disease.

Unfortunately, some patients, like Danielle and her husband, don’t see shades of gray. Rather than looking at probabilities, they see things in black and white. Cure or no cure:

And, if you have any empirical research to add to the already existing mountain of research we do have, please send that our way. Also, please let us know if you have access to a genuine crystal ball or a personal Mount Sinai, otherwise, it may be best to leave the predictive outcomes for God to decide. It may be difficult to accept the decision that Danielle has made in choosing life. I just want you to know, for as long as we have life, we stand beside you in hope and dignity of human life.

“Mountain of research”? More like the University of Google. As I’ve pointed out so many times before, it takes a significant amount of background knowledge to interpret the medical literature, and most people simply don’t have it, no matter how much they think they can just “pick it up as they go along.” Conventional oncologists, being science-based, are obligated to discuss their best estimates of what they can do for a patient and how likely their treatments are to result in cure. Young, on the other hand, is free to cater to fantasy and promise that he can cure diseases that conventional medicine can’t. In other words, he can say that he can cure patients like Danielle without toxicity. Whether he really believes it or is lying, I don’t know, but he can—and does—say things like this. For instance, Young claims that he knows about “natural inhibitors” of HER2 that will cure HER2-positive cancers, even though that there is no evidence that anything he recommends actually does anything of the sort.

Of course, Danielle can’t stay in California indefinitely; so she apparently didn’t. She headed back to Edmonton and has put together her own team of “alternative” medicine practitioners, including a naturopath who has her on on intravenous vitamin C & B12, as well as Mistletoe by injection. She also claims to be using an osteopathic doctor who’s making a cancer vaccine of some sort to help her. Now it’s true that anti-HER2 vaccines are a hot area of research, it’s a really hard thing to do. It takes a large and dedicated team of scientists and clinicians, a facility certified to make biologicals suitable for human use, and a lot of expertise and resources that I highly doubt this osteopath has; that is, unless he’s the principal investigator of a team working on such a vaccine at a major research institution. In other words, Danielle’s bringing Dr. Young’s quackery home with her and finding enablers to help her. Again, I have to wonder what her oncologist thinks. That’s a moral dilemma I’d hate to have to face: Keep following Danielle and ordering tests on her. Maybe the oncologist hopes that once it becomes clear that Dr. Young’s quackery is not working there will still be time to treat her and possibly save her.

I really hate seeing blogs like Danielle’s and stories like hers and others I’ve seen. They make me feel so helpless. I know, using science, reason, and logic, that Danielle has chosen a path that precludes her one and only chance of survival, science-based treatment, in favor of what I consider to be quackery. Her chances might not be that great with conventional therapy. I understand that. I understand, as much as it is possible to understand without actually having cancer myself, the sense of hopelessness she must have felt when she was told she had stage IIIC breast cancer. Unfortunately, her chances following Robert O. Young’s quackery are about as close to zero as I can imagine. Worse, even if conventional therapy can’t save Danielle’s life, it can provide good palliation, something Robert O. Young can’t do. There are few more unpleasant complications of breast cancer than a tumor that grows until it erodes through the skin and turns into a fungating, ulcerating, bleeding, stinking mass on a woman’s chest wall. I’ve written about this before, specifically the case of Michaela Jakubczyk-Eckert. (Note: The photos at the link are not for the weak of stomach.) Not only is Danielle foregoing her one and only shot at survival (and it’s a reasonable shot, too), but she’s giving up her chance for decent palliation and preventing the fate that Jakubczyk-Eckert suffered.

Danielle, I’m afraid, is another cancer tragedy in the making. I only hope that she realizes her error before it’s too late. Her latest report might sound as though things are going well, but it’s the calm before the storm. Even nasty tumors like Danielle’s sometimes go through periods where they don’t grow much or where they even shrink a little. Inevitably, they start growing again. Danielle’s already wasted over three months of time that she could have been using fighting her cancer with effective therapy. I hope there’s still time left for her.

And so it is with x-rays. The latest scare du jour, a recent study out of Yale that claims to show a correlation between dental x-rays and intracranial meningioma — the most common brain tumor and usually benign — has been enjoying widespread attention in newspapers and on the evening news. We don’t know if it will be on Dr. Oz, because we can’t bring ourselves to watch that show, but we feel the chances are good. Other alt-medders will no doubt have collective woogasms over the story and will further incite fear and mistrust into the doctor-patient relationship. In fact, the Mercola website wasted no time in weighing in:

While this study does not necessarily establish causation between dental X-rays and tumors, previous research has also implicated dental X-rays in the development of thyroid cancer, and research clearly shows this type of radiation is not harmless…

Typical alarmist fear-mongering. When has any health care professional claimed that radiation is harmless? This is not cutting edge research; Wilhelm Röntgen, the discoverer of x-rays in 1895 and winner of the Nobel Prize in 1901 for his research in the field, advocated the use of lead aprons for protection from the ionizing radiation way back when. Further, trying to lump one study linking dental x-rays to meningioma to another study linking them to thyroid cancer is taking quite the kitchen sink approach. But if there are multiple alleged possible potential theoretical adverse effects from our dental death rays, it must be true, right?

Well, not so fast. We’re dentists, and unlike many knee-jerkers, we’ve actually read the study and would like to offer a little bit of insight into this before everyone panics. In fact, with respect to Letterman, we’d like to offer our Top Three Reasons Not To Panic:

1. The data is primarily anecdotal. The study authors reasoned that since actual data about people’s radiographic histories is hard to compile (people typically see multiple dentists over their lifetimes, and there is no central repository of radiographs taken), it would be acceptable for epidemiological purposes to simply interview people and ask them to recall what dental x-rays they’d had taken over the years since childhood. Claus et al. claim that people show accurate and unbiased recall of their x-ray histories suitable for drawing inferences decades later, but we have news for you. It is standard procedure for us, as dentists, to ask new patients what sorts of radiographs they’ve had in the last fews years (we will ask your previous dentist for copies to avoid taking them needlessly) and you people are terrible at remembering this sort of thing. Except for people who haven’t seen a dentist at all in years, it’s actually a bit unusual for a patient to accurately tell us what and when their last dentist took, even in the previous couple of years — we usually have to call your previous office to find out. Based on our daily reality, the idea that patients can recall what radiographs they’d had since childhood with epidemiologically useful accuracy seems implausibly optimistic, especially when considering that the sample population ranged from 20 years to 79 years old. This would require an accurate memory and reporting of radiographs taken as far back as the 1940’s and 1950’s in many cases, which we submit is not a valid assumption. In fact, the authors, to their credit, state:

Limitations of this study include the possibility of either under-reporting or over-reporting of dental x-rays by study participants. This is a difficult problem in epidemiology, because, unlike medical care, which (at least within cohorts of patients drawn from health maintenance organizations or similar entities) may be confirmed by a review of centralized medical records, dental care generally is obtained (even for a single individual) from numerous dentists, all of which are outside of a health maintenance organization or hospital-based setting, providing little opportunity for researchers to validate dental reports in a timely or cost-efficient manner. No national database of dental treatment exists within the United States; hence, researchers must rely on patient self-report, despite the potential for bias.

Let’s play a fun game.  We’ll ask you, the astute and intelligent reader of the Science Based Medicine Blog, to recall your dental x-ray history for your entire life.  Can you recall the exact dates when a full series of radiographs were taken?  What about a panelipse?   Corrected tomograms?  Cone beam films? Individual films called periapicals? What about bitewing x-rays?

How did you do?

Not very well, did you?  Well, don’t feel badly; we’re dentists and we wouldn’t be able to recall our own radiographic history from memory even if threatened with homeopathic hemlock!  Asking meningioma patients if they remember having x-rays, and comparing with the memories of people not preoccupied with having brain tumors, is not only inaccurate, but also raises the obvious possibility of reporting bias by the study participants.

We are also concerned that the authors apparently did not survey for other potential confounding factors, such as tobacco history, diet, occupational exposures, etc., or if so, they were not disclosed in the paper. It might even be that having had dental x-rays is correlated with going to the dentist regularly, and that those people are also more likely to see a physician regularly and have a timely diagnosis of medical conditions like meningioma. Or perhaps people who live healthy lifestyles and thus have healthier teeth and gums require fewer dental x-rays over their lifetime. In this scenario, quantitative measurements of dental x-rays are an indirect indication of systemic health, and thus meningioma risk. Who knows, but the point is that there are a myriad of risk factors not considered in this study, and the one variable they attempted to measure was vague and nebulous.

2. The results defy dose response expectations The Yale study reports that meningioma patients are twice as likely than controls subjects to remember ever having had a bitewing x-ray (the most common film used in dentistry), and that more frequent bitewings were associated with increased risk. So far so good. But they found no significant correlation with full mouth series radiographs — a set of 16-20 dental x-rays. Please note that a full series of dental radiographs includes 2-4 bitewings, then adds 14-18 more! The take home message, if this were valid, is that a couple of cavity detecting x-rays may give you a brain tumor, but if your dentist takes an extra dozen or so films instead, you’ll be fine. Dr. Alan Lurie, president of the American Academy of Oral and Maxillofacial Radiology, said “That inconsistency is impossible to understand to me”, and he has a good point.  “I think it is a very flawed study,” Dr. Lurie went on to say.  As reported in the ADA News:

 He (Lurie) characterized at least one outcome of the study—reflected in a table that related meningioma risk to types of dental X-ray examination—as “radio-biologically impossible.”

Said Dr. Lurie, “They have a table, Table 2, in which they ask the question, ‘Ever had a bitewing,’ and the odds ratio risk from a bitewing ranges from 1.2 to 2.0, depending on the age group. Then they asked ‘Ever had full mouth’ series, and the odds ratio risk from a full mouth series ranged from 1.0 to 1.2.

“That is biologically not possible because the full mouth series has two to four bitewings plus another 10 to 16 periapicals. A full mouth series, just to round things off, is 20 intraoral X-rays of which two to four are bitewings. They are showing that one bitewing has 50 to 100 percent greater risk than a full mouth series that has multiple bitewings plus a bunch of other films.”Explaining this gross internal discrepancy is difficult, as the epidemiologic and statistical methods are widely accepted, Dr. Lurie said. He attributes the perceived discrepancy in the data to possible recall bias in the patients involved in the study.

The study also found no correlation with cone-beam CT scans, increasingly used in dental implant treatment and providing the highest x-ray dose of any dental radiograph.

3. Lost in the background. Claus et al. point out that dental x-rays are the most common source artificial source of ionizing radiation, which is true, but omit the fact that they are among the least significant quantitatively. Data published in 2009 in the journal Radiology, puts this nicely in perspective:

Estimated collected effective dose from various sources, U.S. 2005 (thousand person-sieverts)

Take note: in the race to blast the most radiation through your brain, nature is falling a bit behind your hospital, but your dentist can’t get within 2 orders of magnitude of it. That’s why you never see a Superhero (or a Godzilla) mutating out of a dental office to save (or destroy) the world. While hospitals and Mother Nature have veritable radiation bazookas at their disposal, we have but pea shooters.

The reason your dentist is actually such a poor choice for suicide by brain tumor is related not to frequency (what the authors of the study focused on) but to dose. Particularly with current trends toward digital x-ray equipment (which exposes patients to significantly less radiation than film x-rays), the actual radiation dose in a dental x-ray might surprise you (data from the Health Physics Society and from Randall Munroe’s superb infographic):

Dose in microsieverts

We hope this will help you understand why we roll our eyes when a physician reporter on NBC tells the audience that they should be really be refusing x-rays at the dentist. This is dangerous advice coming from someone outside of their field of expertise.

Medical radiation aside, an important question remains: when we all get several hundred μSv of background ionizing radiation through our bodies and brains per year — every year- it seems a bit odd that an extra 10 μSv, even once in your life, would significantly raise your risk of anything to the degree that the Yale study claims.

And One More Thing. We are really getting a bit tired of hearing everyone who publishes or pontificates about x-rays opine sagely that x-rays should only be used where necessary, as if they have invented the concept of radiation hygiene. This implies that physicians and dentists routinely take unnecessary x-rays. But this is not a new idea. Keeping radiation exposure As Low As Reasonably Achievable is a cornerstone of diagnostic radiography, and has been for decades. It’s called the ALARA Principle, and it has been taught to everyone who uses x-rays in Medicine and Dentistry for ages. If you go to your dentist (or your physician) and announce that you don’t want any unnecessary x-rays he or she is NOT going to say “no problem — we never really needed the ones we used to take!”. If he or she is any good, chances are that radiographs are prescribed (and that really is the correct term) because the diagnostic benefits of the bitewing or the angiogram vastly outweigh the risks. It’s good to discuss this with your healthcare provider, but bear in mind that doing many invasive procedures without the benefit of adequate diagnostic radiographs is often regarded as malpractice, and for good reason.

And One More One More Thing. We have devoted most of this blog post pointing out some of the flaws of this study and how it may have adverse effects upon your dental health. We would be remiss, however, if we didn’t point out that the fallout from studies such as these rests squarely upon the shoulders of irresponsible reporting by the media. In a desperate battle for viewers/listeners/readers, these stories are belched to the public uncritically, with fear being the primary angle. Rarely is equal time given to rational responses, and sadly, the personalities who spout the loudest are often physicians contracted with the news networks. This is unfortunate for many reasons; among them being that 1) as doctors, they should know better; they should read the article themselves and be able to interpret it correctly, and 2) their opinion is held in high regard by the public, making our job of discussing it with our patients that much more difficult. We can’t tell you how often we have heard from our colleagues the fallout we’ve received when the Great and Powerful Oz (a cardio-vascular surgeon) informed his disciples that one can effectively whiten one’s teeth with raisins and lemons.  Not only is that patently false; it’s harmful to teeth, as putting something almost as corrosive as battery acid on one’s teeth is generally frowned upon in the dental community..   Stories such as these can often create a wedge in the relationship we dentists try so hard to establish with our patients.

Finally, dentistry is by necessity somewhat more reliant on routine radiographs than other health professions because we deal primarily with hard tissues subject to diseases that are often invisible without some radiographs. Keep in mind that tooth decay and periodontal disease are among the most prevalent diseases of the human race, and early detection and treatment are critical to good oral and systemic health. Without radiographs, we often cannot see decay until it reaches the nerve and kills your tooth, or the impacted wisdom tooth until it has damaged the tooth next door, or the asymptomatic abscess until it puts you in the hospital. Occasionally, we discover pathological processes, including the rare case of oral cancer long before they would manifest clinically. A timely x-ray, even in someone with no symptoms, could save a life.  We as a profession readily accept the radiation burden in a bitewing or full mouth exam because of the obvious benefits for the well being of our patients. When we order any X-ray exam, we have made the determination that the benefit outweighs the risk and the risk of such exams are much less than those risks we commonly accept in daily life. We do not take this responsibility lightly.

So, do dental x-rays cause meningiomas? We have criticized the original article and the reporting thereof, but the fact remains that we don’t know. They might, of course, but unfortunately the article only gives us a smattering of data that may or may not be relevant. The signal to noise ratio contained in this study was too low to be of much use, and it’s hard to understand how higher-dose x-ray exams could be safer than the lower dosed single bitewings, or why far higher doses from other sources would not contribute to the same problem. Hopefully a more thorough study will be done to add to our body of knowledge and either confirm or refute the findings of the original article.

We do hope this has helped pull at least some of you back from the brink of a total freakout about your next dental visit. If you still need more dental fear, stay tuned — we hope to tell you soon about another dire threat from your dentist: silver amalgam fillings.

Dr. Grant Ritchey received his Bachelor’s degree in Human Biology from the University of Kansas in 1982, and his Doctor of Dental Surgery degree from the University of Oklahoma in 1986. He lives in Kansas City, is married, and has two grown daughters. Since 1986, he has maintained a general dental practice in Tonganoxie, Kansas, and was awarded a Fellowship in the Academy of General Dentistry in 1998. Currently, he is working toward his Masters in Education Degree from the University at Buffalo in the Science and the Public program, with an emphasis on the prevalence of alternative medical practices in dentistry.

Dr. Steve Hendry, BSc DDS FAGD, completed an honours degree in Genetics at the University of Western Ontario before deciding to be a dentist when he grew up. He spent summers working in a corn cytogenetics research lab through dental school. Since graduating in 1981, he’s maintained a general dental practice. Steve has always been fascinated and appalled at the scarcity of critical thinking skills in society and, increasingly in his own profession. He is particularly proud of having attained the status of “closed minded” in the eyes of some of his woo-friendly peers.

What exactly is “consumer health”? The book’s preface and the table of contents are available here. They will provide the long answer to that question. The short answer is:

The book’s fundamental purpose is to provide trustworthy information and guidelines to enable people to select health products and services intelligently.

Chapters cover how to separate fact from fiction; how to spot frauds and quackery; advertising issues; dental care; mental health care; a science-based overview of the “CAM” movement, with a separate chapter on chiropractic; nutrition fads, fallacies and scams; weight control; fitness; prevention; major chronic diseases; drugs; skin care; medical devices; issues related to death; insurance; accreditation and licensing of health care facilities and professionals; consumer laws; and much more. It includes self-care advice. It offers historical perspectives and illustrative anecdotes, pictures of bogus devices, examples of misleading advertising, and even some cartoons. A handy appendix lists trustworthy sources of information.

It could serve as a valuable reference for anyone, even sophisticated health professionals. I can’t begin to tell you how much I learned during the revision process: I knew about health and CAM, but I was not as well informed about some of the other subjects covered, like legislation and regulation. Now I know much more.

As the long revision process proceeded chapter by chapter, I frequently read statements that made me wonder “Is that really true?” I looked them up to find that they were indeed true.  As lead author, Stephen Barrett was obsessively meticulous; and we challenged each other in numerous e-mail discussions about whether a given statement could be documented and was adequately based on current evidence. More than once, I told him “That’s not exactly true! You can’t say that.” And after looking at my evidence, he either changed his mind and modified the text or persuaded me that I was wrong. It’s a real pleasure when two professionals can resolve a disagreement by simply examining the evidence, with no interference from belief systems or egos. The total antithesis of what usually happens with CAM proponents.

I don’t take credit for this book, but I’m proud of my contributions to it, and I can vouch for its accuracy. I’m not touting it for financial gain: I was paid a small fixed fee and will get no royalties. Nor am I trying to blow my own horn. The text existed long before I got involved, and my contributions were small. I do, however, personally vouch for the information in the book. It is fact-checked and science-based, and there’s not a word of woo anywhere in it.

• Excedrin for the rare migraine
• Arnica 30CH for bumps and bruises
• Echinacea capsules, when you feel a cold coming on

Today you look in your cupboard, and notice all three products expired last year. Would you still consider taking any of them? Why or why not?

Your answer is probably influenced by a number of factors, including perceptions of risk and benefit. I’ve encountered patients who believe that drugs are less active as they near the expiration date, and others who see expiry dates solely as marketing ploy from Big Pharma. Few understand how they’re calculated.

Over the past few months I’ve written several posts on different aspects of drug development and testing, including drug interactions, fillers and excipients in drug products, the equivalence testing of generic drugs, and the management of drug allergies. I’ve done this for two reasons. The first is to develop a SBM-oriented resource for common questions and misconceptions about the mechanics of modern medicines. The second, less obvious reason for these posts has been to illustrate the serious credibility gaps with CAM therapies. Largely because of a lax regulatory framework, the CAM industry has ballooned into a multi-billion dollar market without answering basic questions that should be asked of any supplement or drug, “alternative” or otherwise. What’s not well known to consumers, but is glaringly obvious to SBM advocates, is that CAM largely ignores issues of  pharmacology: understanding how a chemical substance, once consumed, behaves in the body. It’s critical to scientific medicine, but an unnecessary step for CAM, where there’s no need to determine if a product has a beneficial biological effect before selling it. Fundamental tests in medicine, like the identification and isolation of an active ingredient, or understanding dose-effect relationships, are simply ignored. As David Gorski and Mark Crislip have pointed out over the past week, we have a reality bias at SBM.  And this bias is equally jarring when it comes to considering expiry dates for products: real drugs, and also CAM.

Expiry dates are the source of a lot of questions to pharmacists. Not only is the pharmacy legally responsible for ensuring your prescription is filled with “in-date” stock, we’re regularly confronted with dealing with expired drugs. Because of expiry dates, an enormous quantity of drugs are manufactured and sold or dispensed, but never consumed. This creates a significant wastage issue: Last month, the U.S. Drug Enforcement Administration’s  National Prescription Drug Take-Back Day collected 552,161 pounds (that’s 276 tons) of unwanted or expired drugs. Those are drugs that someone paid for, and are now being incinerated. If expiry dates are nonsense, extending them could have considerable economic and environmental benefits. So where does the expiry date come from? For drugs, they’re based on the chemical characteristics of the product itself.

Calculating the expiry date

At some point after major clinical trials are concluded, but before FDA approval, a series of quality standards are established for each new drug. These are the manufacturing and testing specifications, which includes upper and lower limits for the amount of the Active Pharmaceutical Ingredient (API) in each dose unit (e.g., 500mg per tablet). The final dosage form may be a mix of the API as well as fillers, binders, and other ingredients to ensure the API is delivered to the body in a reliable and predictable manner.  But what certainty do we have that this new dosage form will maintain all of these properties over time?  What happens after it sits on a shelf for two or three years, or more? Few companies have the patience to wait, so drug products are put through accelerated degradation testing, or “stress” testing, to estimate how quickly a drug will deteriorate. Depending on the dosage form, stress testing may include short-term exposure to extremes of heat, light, oxidation, and humidity. After exposure over different time periods, the quantity of the API, and the other product characteristics, will be assayed again. Not only does this help us understand how stable a drug is, it illustrates the degradation pathways – what chemical reactions that could be expected to occur over time. For liquid and injectable drugs, there will be additional tests for bacterial purity and chemical stability. All of these tests predict the overall stability of the dosage form – not just the amount of  drug, but how that drug will be absorbed into the body. All of this is used to estimate what the expiry date should be: the date to which the manufacturer warrants the original product characteristics will be retained.

Expiry dates for drugs can vary dramatically. One of the shortest for a drug in common use is injectable epinephrine known as the “Epipen”, carried by those with severe allergies. Epinephrine for injection is notoriously unstable, and you’re lucky to find a product that expires longer than 18 months after you get it.  Other drug products are highly sensitive to moisture, requiring dispensing in specialized containers with dessicants to trap moisture and enhance stability. Many liquid antibiotics have very poor stability, so they must be prepared in the pharmacy at the time of dispensing. Refrigeration is necessary for other drugs, ranging from vaccines to eyedrops, which keeps the dosage form stable.

It is important to keep in mind that the expiry date of a drug is based on testing of previously unopened products, stored in its original container, and maintained under typical conditions. Once you open a bottle, or transfer it to another container (like a prescription vial), the manufacturer’s expiry date is no longer reliable. That doesn’t mean a drug will become ineffective rapidly, but the stability could be compromised once it has been introduced to light, heat, and humidity. Humidity’s effects are frequently noticable with old bottles of Aspirin (acetylsalicylic acid) which breaks down via hydrolysis to salicylic acid and acetic acid giving old bottles a characteristic vinegar odour.

Are expired drugs still safe?

The first concern related to expired drugs is whether they are potentially harmful if consumed. Reassuringly, there is no published data to suggest harms from use of drug formulations after their expiry data. The example of degraded tetracycline causing kidney damage in cases dating back to the 1960′s, is drilled into every pharmacist’s brain. Reassuringly, this occurred with a version of the drug that is no longer available. While recognizing that case reports are an inaccurate and imprecise way of identifying harms, the lack of documented harms suggests that degradation of useful chemicals into toxic compounds is rare, if it occurs at all. Additionally, current requirements for stability testing of drugs should identify if expired products pose a safety risk – and there do not seem to be any other documented cases.

Are expired drugs still effective?

Again, the evidence is reassuring – with some caveats. The best way to verify long-term stability would be to stockpile supplies, let them sit for years, and even decades, and then test them. My American colleagues can thank their government for doing just such testing- the Department of Defense/FDA Shelf Life Extension Program has been in place for over 20 years. It tested 122 different products, stored unopened and in their original containers, and found that about 88% are stable for at least one year after expiry with an average of 5 years after the expiry date. However, this was under ideal conditions – not typical use consumer use, where bottles are usually partially consumed, and partially exposed to moisture and light. Stability isn’t always a given. Epipen’s active ingredient degrades consistently after the expiration. So I’d never suggest people carry an expired Epi-Pen – but I wouldn’t hesitate to recommend its use in life-threatening anaphylactic situations where no other alternatives existed. Similarly, you may be less concerned about drug potency if you’re taking something like Excedrin for a headache, versus medication to treat epilepsy, where small changes in the dose delivered could affect drug levels. Because of sterility concerns, you should throw out an eye drop that has been open for several months, even if the expiry date still says it’s OK to use – that expiry date was for unopened drug.  And if you leave your prescriptions to cook on the dash of your car in the hot sun (I have encountered this) speak with a pharmacist who may be able to get drug-specific stability data.

Disposing of expired drugs

I was surprised to see that the FDA suggests some drugs can be safely disposed of by flushing down the toilet. I could not find similar guidance in Canada, where medication return programs are common and many pharmacies participate. Return program incinerate the drug, eliminating secondary environmental exposure. This method also minimizes the risk of diversion or accidental poisoning.

Revisiting our vignette

Excedrin is a combination of acetaminiophen (Tylenol), acetylsalicylic acid (Aspirin) and caffeine. Excedrin may be effective after expiration – but sniff for the vinegar odour, which indicates the ASA has deteriorated.  Expired Excedrin is unlikely to be harmful, but has the potential for degradation over time.

Arnica 30CH is a homeopathic product. It has no active ingredients, and no meaningful therapeutic effects, so there’s nothing to “expire”. However, regulators like Health Canada insist that an expiry date must be assigned:

Expiry date: The earlier of:

the date, expressed at minimum as a year and month, up to and including which a NHP [Natural Health Product] maintains its purity and physical characteristics and its medicinal ingredients maintain their quantity per dosage unit and their potency; and
the date, expressed at minimum as a year and month, after which the manufacturer recommends that the NHP should not be used.

Given homeopathy, once diluted to typical concentrations, contains zero active ingredients, I’m curious why Health Canada allowed language like “medicinal ingredients” and “quantity per dosage unit” for establishing standards for what are quite literally sugar pills. The FDA, to its credit, recognizes that the non-ingredients of homeopathy can’t be measured and can’t expire:

1. Section 211.137 (Expiration dating) specifically exempts homeopathic drug products from expiration dating requirements.

There’s no good evidence to demonstrate echinacea is effective for preventing or treating colds. The active ingredients, if any exist, have not been identified and isolated. Capsules of echinacea usually contain pieces of the root or rhizome. Given the active ingredient isn’t known, there’s no way to test for its presence. And if you can’t verify the amount of active ingredient in each capsule, you can’t verify its stability over time. So for herbal products without standardized active ingredients, any expiry date is going to be arbitrary – unrelated to product quality or safety. Not surprisingly, the FDA does not require expiry dates to be placed on dietary supplements, an acknowledgement that you can’t verify what you haven’t found. In contrast to the FDA, Health Canada requires an expiry date to be assigned for herbal products.

Conclusion

There’s no single rule for expired drugs and supplements, owing to the variety of products, regulatory requirements, and other factors that can influence a product’s safety and efficacy. In general, expiry dates are conservative, and consumers can have confidence that drug labeling claims will be accurate up to, and in some cases well beyond, the labelled expiry date. The reality is that we don’t store drugs under ideal circumstances. So when absolute certainty is required, stick to drug products that are not expired. When absolutely necessary, expired drugs are probably safe, however, the potency may be compromised. And when you’re talking about supplements, herbals, and homeopathy, keep in mind that any expiry dates are usually arbitrary. And before you flush or toss those expired drugs, find ways to dispose of them in a way that minimizes the environmental impact and potential for harm.

An interesting side effect of this dilemma is a renewed focus on the cost effectiveness of medicine. Effectiveness alone is not enough. We simply cannot afford, for example, to introduce a very expensive treatment for marginal improvement in outcome in a common disease. Different options can also be compared not only for their safety and efficacy, but for their cost effectiveness. In other words, we need to use cheaper alternatives when available rather than always reaching for the latest and greatest (and most expensive) treatment.

This situation provides an opportunity for science-based medicine. Treatments that are promoted as complementary and alternative (CAM) are often sold as cost effective because they are less expensive up front than standard medical care. We cannot, however, cede this argument to proponents of dubious therapies. Cheap does not mean cost effective. You have to be effective in order to be cost effective, and most of the dubious treatments that are marketed under the CAM umbrella are ineffective.

Regulators in Australia seem to get this. ABC news (that’s the Australian Broadcasting Corporation) recently reported:

Natural therapies found to be clinically ineffective will be cut out of government-funded private health insurance rebates.

Treatments including homeopathy, aromatherapy, ear candling, crystal therapy, flower essences, iridology, kinesiology and naturopathy could be found ineligible.

This is good news, however I think labeling this as focusing on “natural therapies” is counterproductive. Such labels are often misleading, inaccurate, meaningless, and a distraction from what really matters – the scientific evidence. What is “natural” about sticking a candle in your ear and burning it to suck out the toxins (which look suspiciously like burned candle wax)? “Natural medicine” is just a marketing term without a useful or meaningful operational definition. Proponets of these dubious methods are using the label to criticize this measure. Also from the ABC article:

However, Australian Traditional Medicine Society president Dr Sandi Rogers says the announcement came as a surprise.

“It’s a little bit of a shock when we as a profession have not been consulted,” she said.

“If this cost-cut is saying ‘we don’t want to spend taxpayer’s money on natural medicine’, I would be very concerned.”

They are spinning this as an attack on “natural medicine.” Rather, the measure is saying that taxpayer money should not be spent on therapies that are not adequately science-based, whether or not they are thought of as “natural”, “traditional”, or “conventional”. All of the modalities listed above are highly implausible and without evidence to support their efficacy.

Concerns about cost effectiveness and public funding are a great opportunity, in fact, to have a public discussion about the efficacy of such treatments. I want everyone to know exactly what homeopathy is (implausible treatments based on magical thinking diluted into non-existence), and I want them to know what the scientific evidence says – that it doesn’t work. Let us then have a frank debate about whether or not the FDA should be approving homeopathic potions, and whether our limited public health care dollars should be wasted on them.

This comes back to the notion that there should not be any double standard when it comes to medicine. CAM proponents usually try to turn this around, claiming they are not being treated fairly. Dr. Rogers, for example, is quoted as saying:

“We would just like a fair playing field.”

I don’t believe that is true. CAM proponents want a double standard with unfair advantages given to so-called CAM therapies. That is the real purpose of the existence of such labels, all created by proponents in order to argue for the double standard. Defenders of science-based medicine are arguing for a single science-based standard in evaluating medicine. We should apply this same standard when considering cost-effectiveness and public funding. CAM therapies should be held to the same standard of plausibility and scientific evidence, and not be given special consideration because they are “natural.” CAM proponents should also not be allowed to change the rules of evidence as they go along in order to rig the game in their favor.

What is amazing is that public rebates were being given for things like iridology (a completely pseudoscientific form of diagnosis), not that they are now going to be taken away.

The cost effectiveness debate is a good opening for proponents of SBM to make the case to regulators that they should not be wasting taxpayer health care dollars on treatments that are not supported by evidence. I hope this the start of a trend. The principle is very simple – we cannot continue to waste resources on pseudoscience in medicine.

Kane recognizes that a major objection to homeopathy is that, at high potencies, not a single molecule of the starting material is present. He says his study found nanoparticles of the parent metal in 200C dilutions of metal-based remedies. He says his findings represent a paradigm shift. In other words, there really is something there when we assumed there wasn’t.

The Study

They purchased samples of 6 homeopathic medications from market sources.  The labels said they contained either 30C or 200C dilutions of gold, copper, tin, zinc, silver, or platinum. They analyzed these medications and found nanoparticles of the corresponding metals. They identified them with TEM (Transmission Electron Microscopy), SAED (Selected Area Electron Diffraction), and ICP-AES (inductively coupled plasma-atomic emission spectrophotometry). I don’t understand the technology, and the published pictures just look like meaningless blobs to me, but for the purposes of this discussion I’ll accept that they reliably identified the presence of the metallic elements.

The Speculation

How to explain the presence of nanoparticles?  They speculate:

1. Shearing forces could have produced them during the manufacturing process, both from mechanized lactose triturations and human-powered succussion.
2. Acoustic cavitation during the manual succussion process could have produced localized bubbles with temperatures high enough to melt metal particles.
3. The nanoparticle-nanobubble complex rises to the surface and forms a monolayer, and it is this top 1% that is collected and used for the next step in the dilutions.

Problems

• They didn’t really know what they were studying. They didn’t verify that the contents of the products they purchased actually conformed to the labels or were prepared by the methods they speculate about.
• They didn’t use any controls. Ideally, they would have used two kinds of control samples: one prepared by the same dilution methods but without any starting material, and one prepared with the same starting material but without succussion. And maybe another homeopathic remedy not based on metals.
• They didn’t rule out contamination of the original products during the manufacturing process or subsequently from something in their lab (airborne contaminants, improperly washed equipment, etc.).

Biggest Problem

Even if nanoparticles are found in homeopathic remedies, the amount is too tiny to expect any effect on human physiology, and the remedies have not been shown to have any therapeutic effect.

He Offers to Answer Any Question

In his e-mail, Dr. Kane said:

I will be deligted to answer any question.i do hope you forward this finding to both the eblievers and sceptics. [sic]

I did have some questions, and I asked them in an e-mail:

1. Why no controls? Without them, can you be sure that there was not some contamination in the manufacturing process that would give the same findings for other homeopathic remedies or that some unrecognized contamination during your experimental preparation might give the same finding for non-homeopathic control samples?
2. How do the amounts you detected compare to the trace presence of other contaminants, such as minute particles suspended in the air that might fall in?
3. Even if your findings are replicated in other labs, what would that have to do with the claims of homeopathy to affect human health?

His Offer Retracted

It seems he had lied: he was not delighted to answer my questions. In fact, he flat out refused, saying 

Yur response is typical of a sceptic who has a totally closed mind and refuses to see any new information. I have coe across many such and in my experience, it is best to leave them alone. [sic]

His attitude says it all. This is not the response of a scientist.

Another Opinion

I asked Dr. Joe Schwarcz,  McGill chemistry professor and science popularizer, to review the paper. He said:

It certainly doesn’t prove that homeopathy works…the question is …does it prove anything?  Frankly I don’t believe the data.  They found some sort of experimental artifact…  

Conclusion

This is just another pathetic effort to validate homeopathy by showing the remedies are more than water, similar to the recent effort by Luc Montagnier. Such studies never seem to get confirmed in other labs or to build towards any coherent body of knowledge. Publishing an uncontrolled study like this says a lot about the editorial and peer-review standards of the journal. Anyway, whatever anomalies proponents might discover in homeopathic remedies, that’s a far cry from establishing that homeopathy has any clinical effects.

Mine! Mine! Mine! I tell you!

My extreme territorial tendencies (even towards my friends and colleagues) notwithstanding on this issue aside, if you read Mark’s post (and if you didn’t go back and read it now—seriously, go now), you might also remember that he was discussing a “reality bias” in science-based medicine (SBM), a bias that we like to call prior plausibility. In brief, positive randomized clinical trials (RCTs) testing highly implausible treatments are far more likely to be false positives than RCTs testing more plausible treatments. That is the lesson that John Ioannidis has taught us and that I’ve written about multiple times before, as have other SBM bloggers, most prominently Kimball Atwood, although nearly all of us have chimed in at one time or another about this issue.

Apparently a homeopath disagrees and expressed his disagreement in an article published last week online in Medicine, Health Care, and Philosophy entitled Plausibility and evidence: the case of homeopathy. You’ll get an idea of what it is that affected us at SBM like the proverbial matador waving his cape in front of a bull by reading this brief passage from the abstract:

Prior disbelief in homeopathy is rooted in the perceived implausibility of any conceivable mechanism of action. Using the ‘crossword analogy’, we demonstrate that plausibility bias impedes assessment of the clinical evidence. Sweeping statements about the scientific impossibility of homeopathy are themselves unscientific: scientific statements must be precise and testable.

Scientific. You keep using that word. I do not think it means what you think it means. Of course, his being a homeopath is about as close to a guarantee as I can think of that a person doesn’t have the first clue what is and is not scientific. If he did, he wouldn’t be a homeopath. Still, this particular line of attack is often effective, whether yielded by a homeopath or other CAM apologist. After all, why not test these therapies in human beings and see if they work? What’s wrong with that? Isn’t it “close-minded” to claim that scientific considerations of prior plausibility consign homeopathy to the eternal dustbin of pseudoscience?

Not at all. There’s a difference between being open-minded and being so “open-minded” that your brains threaten to fall out. Guess which category homeopaths like Rutten fall into. But to hear them tell it, homeopathy is rejected because because we scientists have a “negative plausibility bias” towards it. At least, that’s what Rutten and some other homeopaths have been trying to convince us. This article seems to be an attempt to put some meat on the bones of their initial trial balloon of this argument published last summer, which Steve Novella duly deconstructed.

Before I dig in, however, I think it’s necessary for me to “confess” my bias and why I think it should be your bias too.

In which I confess my bias

Regular readers might have noticed that we write about homeopathy a lot on this blog. You might wonder why. Indeed, sometimes I myself wonder why. After all, if you want to come up with a list of the top three most ridiculous alternative medicine modalities with a large following, surely homeopathy will almost always be on the list, along with energy healing modalities (such as reiki) and a third nutty modality to be named later whose identity will be left for the reader for later given that there is likely to be some disagreement about it.

In any case, among highly implausible alternative medicine “healing systems,” homeopathy is at or near the top of the heap, reigning supreme. After all, given its twin pillars of “like cures like” and the law of infinitesimals, the former of which says that to relieve a set of symptoms you choose a remedy that causes those symptoms in healthy people and the latter of which says that those “like” remedies get stronger if they are highly diluted in serial steps—but only if they are vigorously shaken or “succussed” between each step. The first principle has no basis in physiology, pharmacology, biochemistry, or medicine (the claims of homeopaths to co-opt a real phenomenon known as hormesis notwithstanding), while the second principle so thoroughly violates the laws of chemistry and physics that, for it to be true huge swaths of these disciplines that have been well-established through hundreds of years of experimentation and observation would have to be not just wrong, but spectacularly wrong. One must concede that it’s possible that this latter principle might be true, but the odds that it is are about as infinitesimal as the amount of starting remedy in a 30 C homeopathic remedy. (That’s a 1 in 10⁶⁰ chance, for those not familiar with homeopathy.) For all practical intents and purposes, the chances that homeopathy can work is zero. It is just water with its believer’s magical intent imagined into it.

So ridiculous is homeopathy that I sometimes feel that I and my fellow supporters of SBM are firing Howitzers at an ant when we take so much time and effort to explain why homeopathy is nonsense. On the other hand, it is homeopathy’s monumental lack of scientific plausibility that makes it a perfect teaching tool explaining the difference between science-based medicine (SBM) and evidence-based medicine (EBM). Specifically, because clinical trials have unavoidable shortcomings and biases, even at a p=0.05, which would imply only approximately a 5% chance that a given trial’s apparently positive results could be due to random chance alone. As John Ioannidis has taught us, in clinical trials as practiced in the real world, the chance is much higher that any given positive trial is a false positive. As explained in so much detail by Kimball Atwood, that also means that, the lower the prior plausibility of a remedy working, the higher the chance of false positive trials. This is exactly what we see in homeopathy, hence the panoply of homeopathy trials showing “positive” results in which the treatment group is barely different from the control and/or the results barely reach statistical significance. With something like homeopathy, which violates the laws of so many sciences, it is relatively easy to make the case that it takes a lot more than a few equivocal clinical trials to show that so much well-established science is wrong. Apparently positive clinical trials of homeopathy are measuring, in essence, the noise inherent in doing clinical trials.

Although most physicians and clinical investigators don’t think about it consciously they tend to have a bias for plausible hypotheses and treatments in evidence-based medicine and against implausible hypotheses. This bias is certainly not inherent in EBM, as we have described may times before. EBM, after all, relegates basic science considerations to the very bottom rung of its ladder of evidence, below even expert opinion. Clinical trial evidence and epidemiology are all, and, although EBM aficionados deny it, the way EBM is practiced it does appear to worship the randomized clinical trial (RCT) above all else. In fact, that “plausibility bias” that most physicians have often manifests itself as difficulty believing that there is a problem with EBM, that EBM can go so off the rails when it comes to CAM because it really has no mechanism to take plausibility into account. Indeed, it’s been speculated right here on this very blog that the reason prior plausibility is not built right into EBM, so to speak, is because the founders of EBM suffered from it. They assumed that treatments would not reach the stage of large RCTs if they had not proven themselves plausible first through preclinical evidence in laboratory studies, animal experiments, and studies of pathology and lab tests. Under this view, it simply never occurred to the gods of EBM that something as ridiculous as homeopathy could reach the stage of RCTs because they suffered from plausibility bias that blinded them to the very possibility of that happening!

Whether that’s true or not, I don’t know, but it would explain a lot. Either way, as we have pointed out, SBM tries to restore to EBM what it is missing: A consideration of prior plausibility based on scientific considerations. In practice, this is more useful for eliminating incredibly implausible treatments, such as homeopathy and reiki, than it is for putting hard numbers on prior plausibility for treatments because it is not always necessary to estimate a pre-trial probability of success, except when it so low that it would take an incredible amount of evidence to overturn existing knowledge, as it would for homeopathy or reiki. Here’s my plausibility bias: For something like homeopathy or reiki, either of which would require the rewriting of huge swaths of science to become plausible, I consider it reasonable to require supporting evidence at least in the same order of magnitude of quantity and quality as the evidence showing that homeopathy or reiki cannot work to make it reasonable to start to think that either could work. Or, to put it much more simply, extraordinary claims require extraordinary evidence.

That’s my plausibility bias. I’m biased in favor of science and reason and against magical thinking like homeopathy and reiki. You should be biased too.

The homeopaths attack

After I had stopped laughing in response to seeing homeopaths lecture scientists on what is and is not scientific, I delved into the paper. Rutten et al try (and fail—after all they are homeopaths) to establish their scientific bona fides righ in the second paragraph:

The authors of the present paper are doctors and scientists with an interest in homeopathy, committed to the scientific method in researching and practising it. We are qualified in medicine and science and started practising these in conventional contexts, gradually becoming convinced that homeopathy is an effective option, supplementary to rather than conflicting with conventional medicine. We concur with Hansen and Kappel that the disagreement concerning the interpretation of reviews of randomised controlled trials (RCTs) is rooted in prior beliefs and their influence on the perception of evidence. We do not concur, however, with their assumption that the homeopathy community’s positive view of the evidence is due to a rejection of the naturalistic scientific outlook. We ourselves, for example, do not reject any part of the naturalistic outlook.

My first temptation was to point out that the very fact that they are homeopaths means that they are either deluding themselves or lying when they claim that they do not reject any part of the naturalistic outlook. Homeopathy, after all, is rooted in the principles of sympathetic magic, not science. For instance, homeopathy’s law of similars (“like cures like”) is uncannily similar to Sir James George Frazer’s Law of Similarity as described in The Golden Bough (1922) as one of the implicit principles of magic. In addition, the concept that water can somehow retain the imprint of substances with which it’s been in contact, which really underlies the belief among homeopaths that remedies diluted to nonexistence (basically anything diluted more than around 12 C—14C or 15C, to be safe) can have biological effects, is very much like the Law of Contagion. Read the following passage from The Golden Bough and tell me that it doesn’t sound almost exactly like homeopathy:

If we analyse the principles of thought on which magic is based, they will probably be found to resolve themselves into two: first, that like produces like, or that an effect resembles its cause; and, second, that things which have once been in contact with each other continue to act on each other at a distance after the physical contact has been severed. The former principle may be called the Law of Similarity, the latter the Law of Contact or Contagion. From the first of these principles, namely the Law of Similarity, the magician infers that he can produce any effect he desires merely by imitating it: from the second he infers that whatever he does to a material object will affect equally the person with whom the object was once in contact, whether it formed part of his body or not. Charms based on the Law of Similarity may be called Homoeopathic or Imitative Magic. Charms based on the Law of Contact or Contagion may be called Contagious Magic.

A later passage by Sir Frazer is an excellent criticism of the two pillars of homeopathy:

Homoeopathic magic is founded on the association of ideas by similarity: contagious magic is founded on the association of ideas by contiguity. Homoeopathic magic commits the mistake of assuming that things which resemble each other are the same: contagious magic commits the mistake of assuming that things which have once been in contact with each other are always in contact. But in practice the two branches are often combined; or, to be more exact, while homoeopathic or imitative magic may be practised by itself, contagious magic will generally be found to involve an application of the homoeopathic or imitative principle.

See what I mean when I say that the ideas behind homeopathy resemble sympathetic magic far more than they resemble science? From my perspective, all homeopaths—and I do mean all homeopaths—hold views that reject science, no matter how much they fool themselves into thinking they are scientific and buy into the naturalistic world view. I could go on to demonstrate how much of homeopathy is rooted in prescientific vitalism, using Samuel Hahnemann’s own words, but I think you get the idea. Homeopathy is magic water made magic using thought processes akin to those used in voodoo when voodoo practitioners make voodoo dolls.

It is also rather interesting how Rutten et al are so willing to accept science when it comes to RCT evidence but reject the much larger and far more robust body of science that underlies the pre-trial assessment of prior probability that says that homeopathy can’t work. They willfully reject the concept that extraordinary claims require extraordinary evidence, and homeopathy is nothing if not a highly extraordinary set of claims. Instead, Rutten et al make an analogy to crossword puzzles. This analogy is actually rather apt, but not in the way our unhappy homeopaths think it is. Basically, here is the analogy as described by Rutten et al:

Sometimes new evidence overturns theory, but sometimes not; the context is crucial. This has been expressed in terms of a crossword analogy (Haack 1998): the correctness of an entry in a crossword depends upon how well it is supported by the clue, whether it fits with intersecting entries, how reasonable those other entries are, and how much of the crossword has been completed. In this analogy, for homeopathy, the primary entry is: “Does it work (other than by placebo effects)?” The secondary intersecting entries are concerned with “How does, or could, it work?”

Although Rutten et al will never admit it, this analogy is an excellent one for why the occasional “positive” clinical trial of homeopathy does not overthrow the existing scientific paradigm that concludes that homeopathy can’t work, that it is nothing but water, and that any apparently positive effects seen are due either to placebo, random chance, or bias and/or shortcomings in the RCTs. Such trials do not fit with “multiple intersecting entries” in physics, chemistry, and biology that are all consistent with the impossibility of homeopathy; i.e., they do not fit into the crossword puzzle. The only way they could be made to fit into the crossword puzzle would be if homeopathy were shown in a reproducible fashion to cure incurable diseases, such as metastatic pancreatic cancer, in which case homeopathy might go into the crossword puzzle and force the puzzle solver to start rethinking other answers to fit with homeopathy.

In other words, clinical evidence could make us question the rest of the “crossword puzzle” but only if it’s clinical evidence that is so extraordinary in result, quality, and quantity that it starts to rival the existing evidence from multiple disciplines that do not support homeopathy. No such evidence exists for homeopathy, and, in fact, the overall weight of the clinical evidence is consistent with homeopathy not working any more effectively than placebo. Indeed, Ruten et al wrongly relegate the question of how homeopathy could work to a secondary question, and here’s why: When, for a therapy to work the very laws of physics would have to be, as I say so often, not just wrong but spectacularly wrong, the question of how it could work is not secondary. This is in marked contrast to drugs (which inevitably work by either binding to a biological molecule or otherwise reacting somehow), in which case not knowing the exact mechanism is not as concerning. Even cases like the discovery that H. pylori causes duodenal ulcers is not a refutation of this principle with respect to homeopathy. After all, as implausible as the hypothesis that it was a particular bacterial species that was responsible for peptic ulcers in many cases, it did not require the violation of the laws of physics to imagine that a bacterial infection could somehow cause ulcers.

Rutten et al spend considerable verbiage listing the usual suspects for homeopathy, including old meta-analyses, various clinical trials, and, of course the infamous basophil degranulation experiments by Jacques Benveniste. These have been fodder many times before on this blog; so I don’t really want to dwell on them other than to note that in particular Rutten et al reserve most of their vitriol for a meta-analysis and systematic review of the literature by Shang et al published several years ago in The Lancet that found that homeopathy effects are placebo effects. Basically, Rutten et al basically rehash Rutten’s criticisms of Shang’s analysis. These are criticisms I dealt with in detail, and four years of aging don’t make them any better. In fact, the apologia based on “clinical evidence” is nothing that we haven’t heard before and nothing worth rehashing here (other than a link to my previous deconstruction) because the point of Rutten et al is to attack what they call “plausibility bias.” All the trotting out of clinical evidence that allegedly supports homeopathy is in reality a massively flawed lead-in, a thin mint wafer to cleanse the palate, so to speak, to the main argument, which is based on how Shang’s meta-analysis and other clinical trials allegedly support homeopathy but are often cited as evidence against homeopathy.

First, Rutten et al distinguish between homeopathic dilutions in which there might still be some of the original remedy left (generally less than 12C or so, but in reality any homeopathic dilution that gets higher than 7C (10^-14) is probably in the femtomolar range or lower, and there aren’t very many substances that have significant biological effects at such a low concentration. None of this stops Rutten et al from proclaiming:

There are obvious sources of pre-trial belief. These include well documented paradoxical low-dilution effects. The basic idea of homeopathy is the exploitation of the paradoxical secondary effects of low doses of drugs. Secondly, reverse or paradoxical effects of drugs and toxins in living organisms as a function of dose or time are very widely observed in pharmacology and toxicology. They are variously referred to as hormesis (the stimulatory or beneficial effects of small doses of toxins) hormligosis, Arndt- Schulz effects, rebound effects, dose-dependent reverse effects and paradoxical pharmacology (Calabrese and Blain 2005; Calabrese et al. 2006; Bond 2001; Teixeira 2007, 2011).

Repeat after me: Hormesis does not justify homeopathy. It’s an analogy that homeopaths love because it’s a hypothesis that states that some substances that are toxic at high doses might be benign or even beneficial at lower doses. (Look back to the fun I had with Ann Coulter’s invocation of hormesis to try to convince you that radiation from the Fukushima nuclear reactor is in fact good for you for an explanation.) This is, of course, wishful thinking on the part of homeopaths, representing extreme over-extrapolation. Hormesis might apply to low doses, but much of homeopathy involves no dose; i.e., dilution far, far beyond the point where it is highly unlikely that even a single molecule of the original substance remains. Rutten et al try to dodge this question by claiming that most homeopathic remedies are not “ultramolecular dilutions” (i.e., dilutions far beyond Avogadro’s number that leave nothing behind). Even if that’s true, many homeopathic dilutions are “ultramolecular” dilutions, and homeopathy does postulate that dilution and succussion do increase the potency of homeopathic remedies. Have Rutten et al forgotten the Law of Infinitesimals?

They haven’t, though. After trying to argue that most homeopathic remedies are not “ultramolecular,” Rutten et al then cite a bunch of dubious in vitro studies claiming that ultramolecular dilutions can have biological effects. I’ve looked at many such studies (for instance, this study of homeopathic remedies on human breast cancer cell lines), and quite often what you find is shoddy methodology, effects of solvents and contaminants, and other potential explanations for the observed results that do not involve having to throw out huge swaths of physics and chemistry. Amusingly, Rutten et al even admit that such results have a serious problem:

A more recent meta-analysis evaluated 67 in vitro biological experiments in 75 research publications and found high-potency effects were reported in nearly 75 % of all replicated studies; however, no positive result was stable enough to be reproduced by all investigators (Witt et al. 2007).

Can you say “publication bias”? Sure, I knew you could.

Can you also say: Anecdotal evidence? Sure, I knew you could:

The other major source of our prior beliefs is practice experience. This may be regarded the lowest level of evidence, but it is under-rated by many (Vandenbroucke 2001). After adding homeopathy to conventional treatment, many unsuccessful cases improved (Marian et al. 2008). The repetitive character of such experiences gradually updated our belief, consistent with Bayesian theory (Rutten 2008).

In other words, Rutten et al admitting that the source of their “positive plausibility bias” towards homeopathy is based on anecdotes. That is, after all, what “practice experience” is: Anecdotes, confirmation bias, and the like. It’s the same reason that Dr. Jay Gordon, for instance, believes that vaccines cause autism when the evidence from large epidemiological studies does not support that belief. He sees what he thinks are cases of “vaccine injury” manifesting itself as autism and, because he believes that vaccines cause autism, attributes his patients’ autism to vaccines. Rutten et al also cite non-blinded, non-randomized “real world” (pragmatic) trials as contributing to their pre-test plausibility bias towards homeopathy.

Pre-trial belief: Science versus anecdote

We have argued that EBM has a shortcoming, and that shortcoming is that EBM does not adequately consider prior probability in assessing evidence. In EBM, clinical evidence is all, and evidence from RCTs (or even better, meta-analyses or systematic reviews of RCTs) rules the heap. This is not unreasonable when RCTs are only performed for hypotheses that have been developed through a scientific process that takes preclinical observations and builds upon them, such that existing evidence deems them reasonably plausible. CAM in general and homeopathy in particular are not such a case. RCTs of homeopathy in essence measure noise, but only positive noise. Some studies will appear to be positive, and publication bias will make sure that the studies where patients receiving homeopathy do worse are unlikely to be published so that we see in the literature only negative studies or studies apparently positive due either to random chance, either alone or combined with poor study design and/or bias. We and others have proposed taking prior probability into consideration, both for deciding what hypotheses to test in clinical trials and how to interpret the results of existing clinical trials.

The fact is that we have always taken plausibility into account in deciding which clinical trials to perform. We have to because we don’t have unlimited resources, human subjects, or researchers to test in an RCT every hypothesis that comes along. We just don’t. In fact, our resources are currently more constrained than they have been in at least 20 years, with NIH pay lines hovering around the 7th percentile in some institutes. Moreover, the very foundations of medical ethics as laid down in the Helsinki declaration require that human subjects experimentation have a strong background of basic science backing it up. The question is: How do we want to prioritize which trials get done? On what do we base our estimates of prior plausibility that color our decisions regarding which clinical trials to carry out and how to interpret data from existing clinical trials? Homeopaths like Rutten and colleagues would propose that we base our estimate of prior plausibility on anecdote, magical thinking, and dubious in vitro and clinical trial evidence, ignoring the massive, well-established prior implausibility of homeopathy that a rational scientific assessment will arrive at. Scientists base their assessment of prior plausibility based on as objective as possible an interpretation of existing scientific data.

I know which one I would choose.

I also have a message for Rutten and is merry band of homeopaths. You accuse us of “plausibility bias” as though that were a bad thing. It’s not. As Mark Crislip pointed out, what plausibility bias should really be called is reality bias. We are biased towards reality. Homeopaths are biased towards what they think is reality but is in actuality magical thinking.

Again, I know which one I choose.

Finally, we don’t have unlimited resources to test every hypothesis that anyone can think up. There isn’t the money. There aren’t enough scientists. Even leaving aside the serious ethical problems that come with testing highly improbable remedies on human subjects, there aren’t enough human subjects to test the promising drugs that have a reasonable probability of working (i.e., of being efficacious and safe) based on preclinical testing. Resource constraints have always existed, and scientists have never just tested whatever the heck they felt like testing. Plausibility has always been a major part of deciding which experiments to do, which promising compounds to take to clinical trials, which treatments to try. Think of it this way: We could estimate plausibility as carefully as we can based on scientific testing, evidence published in the existing scientific literature, and data from small pilot clinical trials. Or, taking the approach of Rutten et al, we can estimate plausibility from anecdotal experience, questionable experiments and clinical trials, and considerations that completely ignore the laws of physics and chemistry.

Again, I know which method I choose.

I have been reading 13 Things That Don’t Make Sense by Michael Brooks. The book concerns topics in science that are unexplained by the current understanding  of the laws of the universe or contradict the dominant paradigm. Well, almost.  His final topic is homeopathy, and it is the one topic whose conclusions, while qualified, belong on Failblog.  The first chapter concerns dark matter and dark energy and how what we can see makes up only a small fraction of the content of the universe.  The author discusses the history behind the discovery of dark matter and dark energy, and the theories that attempt to explain the cosmological measurements that demonstrate the dark existence.  Besides new kinds of matter, physicists have hypothesized that the problem is not undiscovered matter but a lack of understanding of the nature of gravity.  He discusses at length the Pioneer anomaly, the fact that the Pioneer space probes, launched in the 1970’s, are not following their projected trajectories and perhaps this was a manifestation of the dark matter/dark energy/modified gravity.  Evidently it wasn’t, the perturbations are probably  due to radiation pressures.

What is striking is the description of the approach to the measurements that led to the hypothesis of dark energy and matter and the Pioneer anomaly. The investigators took extreme care in looking for every possible error within known physical parameters rather than looking for new physics to explain the data.  The lead investigator of the Pioneer anomaly said something to the effect, when you go into something looking for something new, that is what you will see.

I do not have an exact quote, since I am reading (2) the Audible book version, and the one problem with audio books is you cannot underline important quotes.

That is a striking characteristic of the evaluations of observations that contradict the known laws of the universe.  First, the researchers were meticulous at looking into every possible reason for the anomalous results within known laws.  And when they found anomalies, like the paths of stars circling galactic centers that suggesting the presence of dark matter, they carefully peat and repeat the measurements to confirm the findings before releasing the results.

It is the care with which physicist/astronomers and others in the ‘hard’ scientist evaluate the natural world that is impressive.  They consistently rely first on the basic principals that have centuries of careful observation and experiment to validate their approximate truth.  In the case of the Pioneer anomaly, there was no new physics to explain the trajectory, although it took 30 years to find the solution.  In the case of stars orbiting the galactic center and the accelerating expansion of the universe, something unexplained was occurring.  In both cases, a meticulous comparison to known reality was key to the understanding of the validity of the observed phenomena.  They relied on basic principals.

The author also notes what happens when investigators evaluate phenomena with pre-existing ideas as to what they should find.  I have always used the example of N-Rays, but Brooks uses Percival Lowell as an example.  Lowell was an astronomer who was committed to finding a civilization of Mars, and as a consequence saw and mapped a complex canal system on the planet.  The ability to see what you want to be there, rather than what is actually there, is one of the hallmarks of bad science, although in Lowell’s case he may have been inadvertently mapping the vessels of his own eye.  I initially wanted to write an entire entry on the topic of scientific paradolia, but besides N-rays and Mars canals, I could not come up with similar examples.  Freud? Perhaps.

The counter example,  the disasters that result from  ignoring basic principles, and of avoiding repetition and careful measurement was typified by Pons and Fleishman and the cold fusion debacle.  There are phenomena not yet dreamt of in our philosophy, but if you are going to discover results that violate the basic laws of the universe, it had best be measured carefully and consistently reproduced.  Cold fusion does not meet those criteria.

It is quite a contrast with the studies of SCAM modalities.  Most SCAMs have no basis in known physics, chemistry, physiology, anatomy, etc.  Acupuncture, homeopathy, reiki, chiropractic and their ilk are not based in reality but fantasy.  It is the concept of prior plausibility, or what I would call a reality bias (3), that makes any positive findings more likely to error and bias.  It is clear, particularly well delineated with acupuncture, that these modalities have no effect on objective endpoints and only minor effects on subjective endpoints.  Increasingly well designed studies reveal decreasing effects until excellent studies show no effect.  SCAMs  are the medical N- rays and Mars canals.  Yet in medicine, rather than noting that the studies are based in unreality and repeating careful studies that help tease out the biases and mistakes that make most SCAM trials appear to have effectiveness, they open Centers for integrative, alternative and complementary therapies.

It is odd, the blindness of the medical practice for rank nonsense.  Brooks describes the opprobrium that Pons, Fleishman and others received for their trumpeting of imaginary breakthroughs, although I suspect it was not what they did, but how they did it, bypassing peer review in favor of a press release, that led to the pariah status they now apparently have.  Researchers in quackery, rather than exile in France, start Clinics and Institutes.  While the collapse of the careers of Pons and Fleishman et. al as described by Brooks seems excessive for the ‘crime,’ the only consequence  in medicine for practicing magic is cash.

Outside of medicine careful research confirms or denies our understanding of reality.  In medicine, at least with SCAMs to judge from the Bravewell report, reality is ignored.

The last two chapters of the book cover placebo and homeopathy.  In the case of placebo, Brooks is a little sloppy at times at differentiating the difference between subjective and objective outcomes.  In the example of homeopathy he focuses on a few anomalous studies that were never reproduced and a long, and interesting, description of mysteries of water, to wonder about the unknown properties of H2o that could validate homeopathy, all the while admitting homeopathy is, by current understanding, total nonsense.  But as he consistently noted in the prior chapters, anomalous studies that can’t be reproduced and violate the basic laws of science turn out to be nonsense.  Then he ignores the same lessons in his conclusions about homeopathy: based on a bit of popularity of the crowd (how can millions be wrong?) and the fact that since there other anomalies have led to insights, homeopathy may indeed have  something to it.  I doubt it.

Understanding often advances with anomalous studies that are reproducible and where more mundane explanations consistent with known physical laws are excluded. As Asimov noted,  “The most exciting phrase to hear in science, the one that heralds new discoveries, is not “Eureka” but “That’s funny…”  SCAMs remain funny, but not in the way Asimov suggested  As they stand today,  the anomalies of SCAM are no more than error and bias.  If Ioannidis is correct about real medicine, and he is, then he is doubly correct for SCAM research. Instead of learning from past research,  marginally positive results of poorly designed studies are seen as proof of efficacy, despite no prior plausibility for and the opportunities for error and bias are enormous.   And then you charge the ill and vulnerable for the privilege of receiving your nonsense.

Astrology is not taught as a subset of astronomy for good reason.  There is no alternative aviation, complementary engineering or integrative fire fighting.  Medicine is different and it sometimes saddens me.

Notes
1) 3 out of 2 Americans do not understand statistics.

2) Yes, I am reading the book.  Unless you say the blind are feeling the book.

3) Foreshadowing of SBM to come.

First, some background. Back in 1949, the Texas Legislature defined the scope of chiropractic practice as, among other things, “the practice of adjusting the vertebrae to correct any subluxation or misalignment thereof . . .” Over the ensuing years, the legislature amended the chiropractic practice act with an eye toward modernization, resulting in the current scope of practice being “nonsurgical, nonincisive procedures, including, but not limited to, adjustment and manipulation, in order to improve the subluxation complex or the biomechanics of the musculoskeletal system.” Now that’s progress!

Playing by the rules

Texas chiropractors are regulated by the Texas Board of Chiropractic Examiners [TBCE]. Normally, a regulatory body like the TBCE issues rules through a formalized procedure which gives stakeholders a voice in the rulemaking process. Once a rule is enacted, those adversely affected by it can challenge the rule in an administrative proceeding or in court. However, the TBCE for years avoided this process by relying instead on informal “statements” or “memoranda.” The effect of this was to prevent anyone from challenging the TBCE’s interpretation of chiropractic scope of practice.

In 2005, the Texas Legislature forced the TBCE’s hand by requiring it to adopt rules clarifying what is, and what is not, within the scope of chiropractic practice. In doing so, the TBCE would be limited by the Legislature’s definition of chiropractic but there was wiggle room to interpret the practice act as it saw fit. Requiring the TBCE to go through the normal rulemaking procedures would give any opponents of TBCE’s scope-of-practice delineations the chance to test the rules in court. Thus, the TBCE came to issue rules broadly defining chiropractic scope of practice, including authorizing chiropractors to perform needle electromyography, manipulation under anesthesia and vestibular-ocular-nystagmus testing. The rules also appeared to allow chiropractors expansive authority to “diagnose.”

A little too expansive, according to the Texas Medical Association [TMA] and the Texas Medical Board [TMB]. Because they now had specific rules they could challenge in court, the TMA and TMB (which I will collectively refer to, as the appellate court did, as the “physician parties” or “physicians”) sued the TBCE, along with its Executive Director and the Texas Chiropractic Association (referred to collectively as the “chiropractic parties” or the “chiropractors”). The physicians alleged that the TBCE’s rules were too broad and therefore went beyond the authority granted TBCE by the Texas Legislature. They also argued the rules were unconstitutional, a challenge yet to be ruled upon by the trial court and therefore not a subject of the appellate court’s opinion.

Vestibular testing

In a separate ruling, a Texas district (trial) court struck down the TBCE rule allowing vestibular-ocular-nystagmus testing as beyond chiropractic scope of practice. That decision was not part of this appellate opinion, but we’ll briefly look at it. According to the TMA website, its successful challenge was based on the contention that state law did not allow chiropractors to perform vestibular testing, because:

The vestibular system is a component of the inner ear and communicates with the central nervous system. Tests of vestibular function are diagnostic tests designed to evaluate the function and structure of the inner ear and/or brain, and they include hearing evaluations because the hearing and balance functions of the inner ear are closely related.    . . . The vestibular apparatus is not part of the musculoskeletal system because the muscles that connect the eyes to the skull do not ‘move the body’ or ‘maintain its form.’ . . . Chiropractors are not authorized to diagnose medical conditions, including defects in the vestibular apparatus, because the Chiropractic Act does not include the diagnosis of diseases within the definition of chiropractic. Even if chiropractors can use the word ‘diagnosis’ in a rule, any such diagnosis must be limited to the biomechanical condition of the spine and musculoskeletal system.

The court agreed.

Manipulation under anesthesia

Manipulation under anesthesia (“MUA”or “S[pinal]MUA”) is, according to Quackwatch, a

procedure in which a chiropractor performs manipulation while an anesthesiologist keeps the patient asleep. MUA has little appropriate use and is potentially dangerous. Because the normal protective reflexes are abolished, the manipulated joint can be overstretched.

Here is how the health insurance company Aetna describes chiropractic use of MUA,

Within the realm of chiropractic, SMUA is generally performed daily for 1 to 5 consecutive days on an outpatient basis, and is followed by a post-SMUA rehabilitation regimen, which entails 1 week of daily manipulation to maintain joint mobility and avoid re-adhesion of fibrotic tissue. Anesthesia is usually induced by intravenous Pentothal (sodium thiopental), and manipulation of the affected joints takes about 7 to 10 minutes.

Except in narrowly defined circumstances, Aetna considers MUA investigational and experimental, which translates as “we won’t pay for it.” Of course, in cases where the patient’s health insurer won’t pay, the patient pays the full freight, without discounts normally negotiated by the insurer or mandated by Medicare.

I don’t know how much a full course of chiropractic MUA would set a patient back, but add up the cost of the MUA itself, an anesthesiologist, an outpatient procedure facility equipped and licensed to handle administration of anesthesiology, multiply that by 5, then add 5 more days of in-office chiropractic manipulation, and I can imagine we’re getting into thousands of dollars.

Neither the trial nor the appellate court had much trouble deciding that MUA was outside the scope of chiropractic practice as defined by the Legislature. This is because the Legislature had specifically defined (by incorporating Medicare coding as a guide) MUA as a “surgical” procedure. Because chiropractors are statutorily forbidden from performing surgery, the rule permitting MUA fell.

Needle EMG

Needle electromyography measures the electrical activity of muscles. (This should not be confused with surface electromyography, a bogus diagnostic procedure sometimes used by chiropractors to detect “subluxations.”) A needle electrode attached by wires to a recording machine is inserted into a muscle to record the electrical activity. Needle electromyography is used to determine the cause of weakness, paralysis or muscle twitching and to diagnose diseases that damage muscle tissue or nerves, such as ALS or myasthenia gravis.

The trial court found, and the appellate court agreed, that insertion of certain types of needles used in the EMG met the definition of an “incision.” As chiropractors are prevented by state law from performing “incisive” procedures, the rule permitting their use of needle EMG was declared invalid.

To diagnose, or not to diagnose

The physicians also challenged TBCE rules allowing chiropractors to “diagnose,” a privilege is not specifically included in their practice act, which limits chiropractors to “us[ing] objective or subjective means to analyze, examine, or evaluate the biomechanical condition of the spine and musculoskeletal system of the human body” and “perform[ing] nonsurgical, nonincisive procedures . . . to improve the subluxation complex or the biomechanics of the musculoskeletal system.” One has to wonder how performing surgical or incisive procedures, should chiropractors be allowed them, could “improve the subluxation complex,” as the “subluxation complex” is a figment of the chiropractic imagination. The very thought raises the horrible specter of a chiropractor chopping away in an effort to redact a “subluxation” of, say, the second cervical vertebra.

The physicians won on this issue in the trial court, but lost on appeal. As I suggested earlier, this may be a hollow victory for Texas chiropractors.

TBCE rules challenged by the physician parties included:

Rule 75.17(d) Analysis, Diagnosis, and Other Opinions

(1) In the practice of chiropractic, licensees may render an analysis, diagnosis, or other opinion regarding the findings of examinations and evaluations. Such opinions could include, but are not limited to, the following,

(A) An analysis, diagnosis or other opinion regarding the biomechanical condition of the spine or musculoskeletal system including, but not limited to, the following . . . .

The rule then goes on to list pretty much everything one could possibly think of in the way of looking into “the biomechnical condition of the spine or musculoskeletal system,” including:

(i) the health and integrity of the structures of the system;

(ii) the coordination, balance, efficiency, strength, conditioning and functional health and integrity of the system;

(iii) the existence of structural pathology, functional pathology or other abnormality of the system;

(iv) the nature, severity, complicating factors and effects of said structural pathology, functional pathology, or other abnormality of the system;

(v) the etiology of said structural pathology, functional pathology or other abnormality of the system; and

(vi) the effect of said structural pathology, functional pathology or other abnormality of the system on the health of an individual patient or population of patients.

These references to “structural pathology, functional pathology or other abnormality of the system” are apparently designed to encompass the latest iteration of the “subluxation,” known variously as the spinal lesion, joint dysfunction, manipulable lesion, and many other names. This formulation holds that the chiropractor can feel or otherwise detect something significant in the spine and then proceed to correct this significant something, although they’ve never been quite able to explain how what they say they feel or otherwise detect has anything to do with the patient’s problem. Nor have they been able to explain how what they do to this significant something, such as an “adjustment,” makes any difference to the patient’s health. At least that is what I have gathered from explanations of what they do posted in commentary on SBM. If I’m wrong about this, I’m sure I’ll hear about it.

Diagnose, but with limits

Two factors saved this rule from exceeding the scope of chiropractic practice in the appellate court’s view. First, the TBCE has interpreted the word “diagnosis” as synonymous with “analyze,” “examine,” and “evaluate,” which are within the statutory scope of chiropractic practice. Apparently the court thought this put some sort of limitation on their authority to “diagnose.” In other words, the court appears to be saying that “diagnosis” may have a meaning beyond “analyze,” “examine” or “evaluate” to a physician, but whatever that expanded meaning might entail, as long as chiropractors interpret “diagnosis” in this limited fashion, they are within their rights. This may be a distinction without a difference, but it is one the court makes.

Second, the court dismissed the physicians’ concerns that chiropractors defined terms in the rules so broadly that they could include virtually any disease or condition of any part of the body. Apparently unaware of the full extent of chiropractic claims of the near universal effect of spinal “structural” or “functional” pathology on the human body, the court found, over and over, that the physicians’ concerns should be allayed by the limitation to “biomechanical condition of the spine or musculoskeletal system.” To each argument of the physicians that the rules included an impermissible expansion of chiropractic scope of practice, the court replied, in effect: “No, no, chiropractors are limited to ‘biomechanical condition of the spine or musculoskeletal system.’” In other words, the court seemed to think this term meant the same thing to chiropractors as it means to physicians and other health care professionals.

This may prove problematic for Texas chiropractors attempting to extend their diagnoses beyond the “biomechanical condition of the spine or musculoskeletal system” – as these terms are used in medicine — by employing the chiropractic concept of the “biomedical condition of the spine or musculoskeletal system,” that is, to the subluxation or any of its current iterations.

In arguing that the rules permitted an overly broad scope of practice, the physicians pointed to the definition of the “subluxation complex” contained therein:

[A] neuromusculosketal condition that involves an aberrant relationship between two adjacent articular structures that may have functional or pathological sequelae, causing an alteration in the biomechanical and/or neuro-physiological relations of the articular structures, their proximal structures, and/or other body systems that may be directly or indirectly affected by them.

Of course, this is gibberish and most chiropractors well know it is gibberish but refuse to do anything about it, such as, say, letting the state legislatures in on this open secret. That would mean the states would have to redefine chiropractic practice to exclude the “detection” and “correction” of the non-existent “subluxation.”

In any event, the physician’s concern was that in using words like “pathology” and “etiology” the rules employed terminology that referenced the disease process. Because the diagnosis of disease was legally beyond the scope of chiropractic practice, they argued, the rules were invalid. The court disagreed, saying that their argument

presumes that ‘disease’ would extend beyond the biomechanical condition of the spine or musculoskeletal system of the body. This construction, as previously suggested, ignores the plain language of the rule restricting any such diagnosis to the biomechanical condition of the spine or musculoskeletal system. . . .

[R]egardless of whether diagnosis, pathology, or etiology invoke concepts of disease as the Physician Parties suggest, the bottom line is that [the rule] limits chiropractors to diagnoses regarding ‘the biomechanical condition of the spine and musculoskeletal system’ as required by the statutory scope of chiropractic.

The physicians also worried that the rule allowed chiropractors to

diagnose any diseases (pathology) that relate to the biomechanical condition of the spine and musculoskeletal system (redefined [by chiropractors] to include nerves and other tissues), determine their origins (etiology) and provide a prognosis on the disease’s effect.

The court specifically rejected this interpretation as too broad, once again citing the limitation of chiropractic practice to the biomechanical condition of the spine and musculoskeletal system.

Did the Court of Appeals adjust the subluxation?

This apparent limitation becomes even more clear in the court’s discussion of the “subluxation complex,” for which it accepted the TBCE’s definition, repeated here:

[A] neuromusculosketal condition that involves an aberrant relationship between two adjacent articular structures that may have functional or pathological sequelae, causing an alteration in the biomechanical and/or neuro-physiological reflections of the articular structures, their proximal structures, and/or other body systems that may be directly or indirectly affected by them.

[BTW, if anyone can tell me what this means, I would appreciate it. I once asked a friend who is a Ph.D neuroscientist specializing in the spine. He said it was “nonsense” but perhaps there are other views out there.]

The physicians argued that the rule’s subluxation definition would allow chiropractors to diagnose a broad range of “neurological conditions, pathological and neuro-physiological consequences that affect the spine and musculoskeletal system and ‘other body systems’ affected by subluxation.”

In what I view as an interesting limitation on the broad sweep of the chiropractic “subluxation,” the court disagreed that the inclusion of this definition of “subluxation” somehow expanded the scope of practice.

Although the definition of the ‘subluxation complex’ indicates that its existence may have functional or pathological consequences or that it may affect essentially every part of the body, the rule itself only allows chiropractors to render an analysis, diagnosis, or other opinion regarding a subluxation complex of the spine or musculoskeletal system.

To me, this says that a Texas chiropractor diagnosing the existence of a “subluxation” and then rendering an opinion that an “adjustment” of the “subluxation” may have consequences beyond the (once again) “biomechanical condition of the spine or musculoskeletal system” would be outside of his scope of practice. This would prohibit, in my view, a number of current chiropractic practices, such as opining that “adjustments” can be beneficial to asthma, allergies, painful periods, infant colic, bedwetting, otitis media, and any of the myriad other diseases and conditions chiropractors claim to treat. (Oh, wait, they don’t “treat” anything. They simply unleash the body’s self-healing ability.) It would also prohibit “maintenance” care, that is, regular “spinal checkups” and “adjustments” for general health, to the extent these claims extended beyond benefit to the “biomechanical condition of the spine or musculoskeletal system.”

The physicians and chiropractors have not announced whether they will appeal to the Texas Supreme Court. The physicians will have another shot when the district court decides whether the rules allowing chiropractic diagnosis are unconstitutional. Stay tuned.

Offit makes several salient points – the first being that the track record of research into CAM, mostly funded by the NCCAM, is pretty dismal.

“NCCAM officials have spent $375,000 to find that inhaling lemon and lavender scents does not promote wound healing; $750,000 to find that prayer does not cure AIDS or hasten recovery from breast-reconstruction surgery; $390,000 to find that ancient Indian remedies do not control type 2 diabetes; $700,000 to find that magnets do not treat arthritis, carpal tunnel syndrome, or migraine headaches; and $406,000 to find that coffee enemas do not cure pancreatic cancer.”

The reason for the poor track record is fairly simple to identify – by definition CAM includes treatments that are scientifically implausible, which means there is a low prior probability that they will work. If the treatments were scientifically plausible then they wouldn’t be alternative.

CAM proponents argue that the treatments they advocate, like acupuncture, certain herbal remedies, and homeopathy, are not implausible, they are just neglected by mainstream medicine because they don’t fit into the narrow (and profitable) paradigm of “Western” medicine.  This argument, however, is demonstrably wrong. Homeopathy is rejected by the mainstream because our current understanding of physics, chemistry, and biology tell us that it is impossible for homeopathic potions with extreme dilutions to have any physiological effect.

I admit that one benefit of all the research that the NCCAM has funded is to test these two versions of reality. Are CAM modalities scientifically implausible or are they just not being given a fair shake by modern medicine? If the former then research into CAM modalities should be largely negative, if the latter than we should regularly be finding CAM diamonds in the rough. Well, after 1.6 billion dollars of research any score of studies the NCCAM has left behind it a trail of negative studies, such as those listed above. This strongly supports the SBM view that “alternatives” to science-based treatments are not science-based.

CAM research, therefore, is like playing the lottery – the chance of winning is so small it is not significantly different from zero, but if you get really lucky perhaps you may hit upon something. As a society we have to decide if this is a worthy investment of our limited research dollars. To continue this analogy, financial advisers often recommend a range of investments from conservative to risky, but I don’t think they would consider buying lottery tickets part of a sound financial plan.

The first major criticism against doing research into CAM, therefore, is that it is simply a waste of resources – not just research money but all the components of the infrastructure of research. This includes access to sick patients.  Patients who enter into a clinical study of a low-probability CAM modality may therefore not be available to enter into a study of a more plausible treatment.

That most of the studies funded by NCCAM are negative raises another point discussed by Offit – the value of negative studies. Offit acknowledges that negative studies in medicine can be very valuable. It is important to know what doesn’t work, especially if it is a treatment that is already being used. In fact I and others at SBM have argued that journal editors need to make more room in their journals (or at least in the online versions) for negative studies (and also for replications, but that is a separate issue), in order to limit the “publication bias” toward positive studies.

This, I feel, is the one legitimate argument for doing CAM research – the value of solid scientific evidence for lack of efficacy of a treatment that is being promoted, even on the fringe. But Offit raises a very important point – does this negative evidence have any effect on the practice of those who are promoting or using CAM modalities? The answer is largely, no. He gives as examples many supplements, like gingko biloba or echinacea, that continue to have robust sales even after large rigorous studies found they do not work.

There is some wiggle room in the data to spin it in more than one way. NCCAM director Josephine Briggs has argued that negative studies from the NCCAM have decreased the sales of specific herbal remedies, like echinacea. This is true, but the decrease was modest and temporary. Sales figures indicate that echinacea remains a popular herb and overall herbal product sales continue to increase (over $5 billion dollars in the US in 2009).  The relative popularity of specific herbs is affected by large published studies that gain some media attention – but not dramatically.

The real problem is that regulation of herbs and supplements are not adequately tied to scientific evidence. Aggressive marketing can therefore have a greater long term effect on the popularity of a CAM treatment than a published study that the public soon forgets. Also, the media often does a poor job of putting published scientific studies into a proper context. For every large rigorous negative study, there are many small, preliminary, and positive studies. In the media, therefore, the positive will tend to get more headlines and more overall attention, even though their relative scientific value is much lower. The media just reports – “a study showed.”

There are also other issues of concern with CAM research. One is ethics – the ethics of biomedical human research is such that we owe it to people we experiment on to maximize the probability that the experimental treatment will be safe and effective. That is why there is the need for a great deal of pre-clinical and preliminary clinical studies before going to a large human trial. Researchers also have to justify their treatment with sound science that indicates it is plausible, that it is likely to be of benefit to the study subjects.

The entire notion of plausibility, however, was thrown out by the very concept of CAM. Offit argues that many CAM modalities “border on mysticism.” I would argue that many of them are mysticism or thinly veiled versions of faith healing. Not only is there no known mechanism, but there is no known way they can possibly work. It is one thing to not know what receptor is the target of interest for a specific effect of a drug, it is another to violate basic concepts of physics and chemistry.

In other words, some CAM modalities are the equivalent of magic. Is it ethical, therefore, to study magic therapies on human subjects? Does this violate the ethical requirement of informed consent? Even worse, in some cases there is already adequate evidence for lack of efficacy (such as the chelation trial that Kimball Atwood has been criticizing).

Conclusion

There is much to criticize in the funding of medical research into highly implausible treatments – they are a waste of resources with little probability of resulting in effective treatments, while negative evidence is useful, users of unscientific treatments don’t listen very much to the evidence, and there are significant ethical concerns.

I propose that as a society we strike a bargain with the proponents of so-called CAM. We will fund and conduct research into CAM modalities where it is reasonably ethical to do so, but in exchange treatments for which there is evidence of lack of efficacy will be abandoned. Further, regulations for health products (like herbal remedies) will better reflect the scientific evidence. I would prefer that evidence of safety and efficacy would be required before marketing, but failing that the FDA should have the power to remove a product from the market after research shows that it is ineffective (right now the FDA must meet a difficult burden of proof of harm to do so).

So, if the evidence shows that homeopathy does not work, the homeopathic industry will vanish. If a rigorous study shows that chiropractic manipulation does not work for asthma then chiropractors will condemn the practice and stop doing it.

However, if scientific evidence does not significantly affect practice or product sales, then why should we pay for it? Further, if CAM continues to be disconnected from scientific evidence, why should it enjoy any legitimacy?

Is this the G-Spot?

The press release proclaims “Study Confirms Anatomic Existence of G-Spot.” The study itself is titled “G-Spot Anatomy: A New Discovery.”  It was just published in The Journal of Sexual Medicine.  The author, Adam Ostrzenski, is an “internationally renowned gynecologic surgeon” with multiple degrees (MD, PhD, Dr Hab) and many peer-reviewed articles listed in PubMed.

The G-spot, or Gräfenberg Spot, is an area on the anterior wall of the vagina that can be stimulated to produce sexual excitement, stronger orgasms, and maybe even female ejaculation. Its existence is questionable. Wikpedia has an extensive article explaining the controversy and the published evidence, pro and con, with links to the original sources. You can read more than you ever wanted to know about it there, so I won’t bother trying to repeat it here. A 2012 review of the G-spot literature concluded:  

Objective measures have failed to provide strong and consistent evidence for the existence of an anatomical site that could be related to the famed G-spot. However, reliable reports and anecdotal testimonials of the existence of a highly sensitive area in the distal anterior vaginal wall raise the question of whether enough investigative modalities have been implemented in the search of the G-spot.

Dr. Ostrzenski claims to have found the G-spot and taken its picture (above). Believers in Bigfoot and the Loch Ness monster have pictures too. They even had “Bigfoot hair” that later turned out to be synthetic wig fibers. Ostrzenski’s “proof” is no more credible than theirs.

The Study

This “discovery” was based on dissecting out the pictured structure in the cadaver of one (yes, only one !) 83 year old woman who died of head trauma. The dissection was performed in Warsaw, Poland, but I will scrupulously refrain from making any Polish jokes. The author declared it was a G-spot based on visual inspection of the specimen alone; he said it was an 8.1 mm sac-like structure with a head, body, and a rope-like tail that disappeared into surrounding tissues. After excision, it could be stretched to 33 mm.  He said the walls of the structure “resembled fibroconnective tissues and resembled erectile tissues.” Both? Apparently he didn’t even bother to take the most obvious, rudimentary next step of examining slices of the specimen under a microscope (with appropriate staining) to determine what kind of tissue it was.  One wonders if he even preserved the specimen in formalin so histological study might still be possible.  And he doesn’t tell us whether he had tried to find it in other cadavers and failed before this “success.”

Visual inspection of one autopsy specimen? How could he possibly know what it was that he had found? Is this a G-spot structure or something else? During embryological development of the genitourinary system there are structures that form and are reabsorbed: could this be a left-over remnant of that process? Could it be a tumor? A variant of normal anatomy having nothing to do with sexual response? Something else? Why didn’t he look for it in a second autopsy (or, preferably, a whole series) before rushing into print? And even if he could document the existence of a never-before-described anatomical feature, wouldn’t it take something more than simple observation to determine that it was the G-spot?

A Big Oops

In the discussion section of his article, Ostrzenski makes an embarrassing mistake: he claims that the G-spot gene has been identified and has been already incorporated into a GeneChip microarray. That struck me as odd. How could they have identified a gene for a structure whose very existence was in doubt?

The reference Ostrzenski provides for this claim doesn’t support it.  In that reference, G-spot does not mean what he thinks it means. By “G-spot” they don’t mean anything to do with vaginal anatomy: they mean DNA probes containing a contiguous run of 4 or more guanines (base pair nucleotides). They make that clear in the second sentence of the abstract. He read carelessly, and his foolish mistake should have been caught by his editors and peer-reviewers. If I thought to question it and look it up, why didn’t they?

Even If It Isn’t Real, It’s Profitable

Whether or not the G-spot exists, you can buy a sex toy, a curved vibrator, specially designed to stimulate it. And there is even a plastic surgery procedure called G-spot amplification to enhance its sensitivity. The ACOG has spoken out against this operation.  Guess who performs and teaches this surgical procedure, along with a number of other questionable vaginal procedures?

Yep, Ostrzenski himself.

The Hype Begins

CBC News, Science Daily and other news outlets promptly proclaimed “G spot anatomy found.” The very day this study was released, I got a PR e-mail announcing it, proclaiming that the existence of the G-spot had been proven, and offering me an interview with a doctor who would explain “how the discovery of the G-spot will change sex for men and women.” A doctor who, incidentally, does not inspire my confidence because she also happens to prescribe bioidentical hormones and practice anti-aging medicine. The Huffington Post wasn’t so sure this study would settle the debate but commented that 

perhaps knowing it and understanding it goes beyond anything you can dissect or measure. It’s an untouchable pathway to bliss and the cosmos, making it something so much more.

Conclusion

In short, this published study is a junk-science travesty perpetrated by a researcher who has a vested interest in proving there is a G-spot so he can justify operating on it. No one deserving the name of scientist would claim to have discovered a new normal anatomical structure based on a visual inspection of one specimen with no further investigation. The author, the editor of the journal, and the peer-reviewers should all be ashamed of themselves.

Further Thoughts

In contrast to the vaccine/autism manufactroversy, there is a legitimate controversy about the existence of the G-Spot. We don’t have enough evidence to confidently conclude either that it does or doesn’t exist. At this point, I wouldn’t even venture an opinion.

I would argue that it really doesn’t matter very much. Clearly, some women respond to anterior vaginal stimulation, others don’t. This might have other explanations: conditioning, suggestion, experience, variations during embryologic development, the ability of any highly innervated area to trigger orgasm in some individuals, or other factors.

Women might think not being able to find their G-Spot means they are defective. Pursuing the elusive G-Spot might engage men in fruitless hunting expeditions when they could be finding other ways to please their partners and concentrating on spontaneous enjoyment rather than prescribed techniques.

Poor men! They have a hard enough time just finding the clitoris.

The DSHEA accomplishes this by making a seemingly reasonable distinction between food and medicine and twisting it in such a way that allows manufacturers to label all sorts of botanicals and various other compounds, many of which have substances in them with pharmacological activity, and sell them as “supplements” without prior approval by the FDA before marketing. As long as the manufacturer is careful enough not to make health claims that are too specific, namely that the supplement can diagnose or treat any specific disease, and sticks to “structure-function” statements (“it boosts the immune system!”), almost anything goes, particularly if a Quack Miranda Warning is included.

Not surprisingly, given what a big business supplements have become in this country largely due to the DSHEA, manufacturers and CAM advocates fight tooth and nail against any attempt to update the DSHEA to correct some of its more unfortunate consequences. Led by Utah Senator Orrin Hatch and Iowa Senator Tom Harkin, who together make up a bipartisan tag-team in defense of the supplement industry and do their best to block any effort to increase its regulation by the FDA. We saw that most recently when Arizona Senator John McCain, of all people, introduced a bill in 2010 to try to tighten up the DSHEA and was thoroughly slapped down by Orrin Hatch. More recently, not satisfied with how good things are for the supplement industry, another Utah Representative Jason Chaffetz reached across the aisle to Jared Polis, teaming up to introduce the Free Speech About Science Act, which basically seeks to allow the supplement industry to make more liberal claims about its products. All it will need is a “peer-reviewed” paper to support it (Mark and David Geier would do!), and you can claim almost anything. Anything to grow the supplement industry, which is currently around $30 billion a year.

That’s why it’s critical, from time to time, to look at actual evidence, and just last week Maria Elena Martinez, PhD, of the University of California San Diego, and co-authors did in a commentary published online in the Journal of the National Cancer Institute entitled Dietary Supplements and Cancer Prevention: Balancing Potential Benefits Against Proven Harms.

As several of us have pointed out before, there are science-based roles for supplementation. For instance, in the case of nutritional deficiencies, and Martinez et al point out the very same thing:

Clearly, dietary supplements are useful for the treatment of nutrient deficiencies; however, with the exception of select subgroups (2,3), such deficiencies are relatively uncommon in the United States and most industrialized countries today.

Of course, if you listen to CAM promoters and supplement manufacturers, you’d think that supplements are absolutely essential to preventing cancer. While it is true that there is increasing evidence that diet has a significant effect on our risk for various cancers, this evidence is nothing new. We’ve simply concentrated on it more in recent years, and a new generation of “natural health” advocates, such as Dean Ornish, have attributed near magical powers to diet as a tool for preventing cancer. As a byproduct of increasing evidence that cancer risk is influenced by lifestyle choices, it is understandably tempting to think that we could somehow “bottle” what’s in various foods as supplements that could reverse or ameliorate diet-associated cancer risks. Ironically, although CAM advocates would never concede it, this sort of thinking is the sort of thinking they themselves decry in conventional medicine when they make the exaggerated charge that all doctors do (or want to do) is to prescribe a pill to deal with health issues. Think about it: Even is supplement did what is claimed for them, is there any real difference between just prescribing a supplement to decrease cancer risk rather than recommending much harder lifestyle interventions and prescribing a statin to prevent heart disease rather than recommending much harder lifestyle interventions?

Martinez et al then go on to summarize the state of evidence as it currently exists for the use of supplements to prevent cancer. They conclude that there is precious little evidence for efficacy and existing evidence for harm. Their assessment of the evidence for antioxidants is particularly withering:

Several early observational studies (10–13) found that diets high in fruit and vegetables were associated with diminished risk of several cancers, including respiratory and gastrointestinal cancers. The importance of β-carotene and other carotenoids was suggested by both retrospective and prospective studies showing that low levels of β-carotene in the serum were associated with higher subsequent risk for lung cancer (14). At one point, research focused on retinoid supplementation, in light of the finding that β-carotene is converted to retinol (13). It was hypothesized that the lower risk associated with consumption of these foods, and with β-carotene, α-tocopherol, and vitamin C intake, might be attributable to the activity of antioxidants. In vitro and in vivo studies suggested that these compounds encourage growth of normal tissue and block growth of abnormal tissue (2). However, human experimental studies have uncovered the following: β-carotene does not prevent non-melanoma skin cancer recurrence (15); β-carotene and α-tocopherol with vitamin C do not protect against adenoma recurrence (16); β-carotene and vitamin A do not protect against lung cancer incidence (17); α-tocopherol and β-carotene do not prevent lung cancer (18); β-carotene does not prevent lung cancer (19); vitamins C and E do not protect against total cancer incidence (20); and α-tocopherol, vitamin C, and β-carotene do not protect against total cancer or cancer mortality (21). Based on a review of trial data, a Cochrane report (22) concluded that there was no convincing evidence that β-carotene, vitamin A, vitamin C, or vitamin E supplements, given singly or in combination, prevent gastrointestinal cancers.

That’s not all, though. An article such as this can’t go without mentioning the Selenium and Vitamin E Cancer Prevention Trial (SELECT), which was resoundingly negative. Selenium and vitamin E showed no evidence of decreasing the risk of prostate cancer, leading to the trial being halted after approximately 5.5 years of followup. Consistent with the results of SELECT, a Southwest Oncology Group (SWOG) trial showed that selenium supplementation in men with a premalignant precursor of prostate cancer showed no benefit, and another trial showed that selenized yeast does not prevent recurrence of stage I non-small cell lung cancer. As Martinez et al put it, “organic selenium appears to provide no cancer prevention benefit.”

Not every trial was negative. One exception noted by Martinez et al is a 20 year old prevention trial in China consisting of 30,000 subjects. This study showed a 13% reduction in cancer mortality, including a 21% reduction in gastric cancer mortality, compared to placebo controls in a randomized trial testing a combination of β-carotene, vitamin E, and selenium. This is, at best, a modest effect. However, similar studies looking at such cocktails were even less convincing, including a companion study of 3,000 subjects examining a supplement that contained 14 vitamins and 12 minerals, including β-carotene, vitamin E, and selenium. No statistically significant effect on cancer incidence was observed.

The counterweight to the weight of existing high quality evidence looking at antioxidants and cancer, which suggests no benefit in the vast majority of cancers studied this far and equivocal evidence even in the handful of studies that suggest a benefit is a cohort of studies that suggests the real possibility of harm due to antioxidant use:

Several antioxidant trials (17,18,30,31) have actually reported increased risks with supplementation. The most prominent example, β-carotene and lung cancer, was tested in two RCTs (17,18) in high-risk populations of heavy smokers and asbestos-exposed individuals. Individuals randomly assigned to β-carotene in the Beta-Carotene and Retinol Efficacy Trial (CARET) trial had a 39% increase in lung cancer incidence compared with those in the placebo arm (17); the ATBC trial found a 16% increase in risk of lung cancer associated with β-carotene (18). With prolonged follow-up, NPC investigators found that selenium supplementation statistically significantly increased the risk of squamous cell skin cancer by 25% and total non-melanoma skin cancer by 17% (30). The increased risk was particularly marked among individuals in the highest tertile of circulating selenium levels just before the start of the trial. The most recent illustration of the possibility that pharmacological doses of antioxidants may not have the intended effect comes from the extended follow-up in the SELECT trial, which reported that α-tocopherol increased risk of prostate cancer by a statistically significant 17%; these results led the authors to conclude that consumers should be skeptical of health claims related to unregulated over-the-counter products (31).

The authors then looked at folate supplementation. The state of the evidence for whether folate can prevent cancer is similarly disappointing. In fact, it can be described as largely negative. Worse, like the case with antioxidants, contrary to the hypothesized benefit of folic acid supplementation, there is evidence that it can contribute to some cancers. For instance, there is one trial that showed that long-term supplementation with folic acid increases the risk of advanced colorectal adenomas (relative risk = 1.67) and the risk of developing three or more such adenomas (RR = 2.32). An elevated risk of prostate cancer was also observed. These results are consistent with preclinical studies in animals suggesting that folic acid can increase the risk of cancer, as well as observational studies that have linked higher dietary intake with an increased risk of prostate and breast cancer. Ironically, in the U.S. and other countries, the government has mandated folic-acid fortification of the food supply, which makes the question of whether folic acid supplementation is doing more harm than good particularly pertinent. True, there’s strong evidence that folic acid supplementation of the diet in pregnant women can decrease the risk of birth defects, particularly neural tube defects, but that is short term supplementation compared to long term supplementation. The question, then, is, as always: Is the balance of benefit versus risk due to folate supplementation favorable? There’s enough evidence out there to be concerned that the answer to that question might very well be no, except for pregnant women.

Finally, Martinez et al take on the case of vitamin D and calcium. Anyone who’s been reading CAM-friendly websites these days probably knows that vitamin D is currently viewed by many in the alternative medicine world as some sort of panacea that prevents all cancer. Heck, to listen to some CAM advocates tell it, vitamin D is supposedly so awesome that it prevents influenza more effectively than the influenza vaccine. Of course, as has been discussed on this very blog, the picture is, as is usually the case, more complicated than that, and Martinez et al try to communicate that complexity, referencing the Institute of Medicine’s recent recommendations for vitamin D and calcium intake published in 2011, in which the IOM concluded that there is insufficient evidence to conclude that there is a causal association between low vitamin D intake or low blood 25 hydroxy (OH) vitamin D [25(OH)D] levels and cancer. Martinez et al sum up this data thusly:

There have been many epidemiological investigations of blood 25 hydroxy (OH) vitamin D [25(OH)D] concentrations and cancer-related endpoints (45–49), and meta-analyses of these have shown statistically significant inverse associations between serum 25(OH)D and colorectal adenoma (46,49) and colorectal cancer (45), whereas the results for prostate cancer have largely been null (45,48). For breast cancer, the relationship with serum 25(OH)D levels varies by study design; case-control studies generally demonstrate inverse associations, and prospective studies have been null (45,47,50); because blood levels are collected after the onset of cancer in case-control studies, the potential for bias in these studies must be considered (47,50). Clearly, clinical trials are needed to elucidate any preventive effect of vitamin D (51,52). To date, three short-term RCTs of vitamin D and cancer endpoints (52–55) have been completed; one showed no direct effect of vitamin D supplementation on cancer mortality (53), the second showed no reduction in breast or colorectal cancer incidence by a vitamin D/calcium combination (54,55), and the third showed a reduction in total cancer incidence by a calcium/vitamin D combination vs placebo (56). As concluded in a recent meta-analysis, because of the potential confounding inherent in observational studies and the limited data from clinical trials, evidence is currently insufficient to draw conclusions about the efficacy of vitamin D supplementation for cancer prevention (57).

As far as cancer is concerned, there just isn’t a whole lot of data from well-designed randomized clinical trials testing the effect of vitamin D supplementation on cancer risk to hang one’s hat on. The same is true of calcium supplementation, only more so. Observational studies have, as Martinez et al almost drolly characterize it, “yielded diverse results.” In any case some of the diverse results with respect to vitamin D suggest a correlation between high vitamin D concentrations and pancreatic cancer, while a recent meta-analysis suggests a reduction in risk. In the case of prostate cancer, however, a recently published study suggests a statistically significantly increased risk of prostate cancer (RR = 1.56 for men in the highest quintile) among men who have the highest levels of 25(OH)D, a finding that was more striking for aggressive disease, leading the authors of the study to advise caution in recommending vitamin D for cancer prevention. Puzzlingly, these results are in contrast to a lot of basic science research that supports a beneficial role for vitamin D compounds in prostate cell proliferation and differentiation, prostate cancer cell growth and invasion, and tumorigenesis.

To say that the state of evidence in support of the use of various dietary supplements as cancer preventatives is unsettled is a gross understatement. Martinez et al discussed supplements that have been studied the most and, let’s be frank, that involve the purest supplements, most of which contain only a single ingredient, and they found little evidence of efficacy in preventing cancer but some evidence of potential harm. That’s not even counting the near innumerable supplements now being sold that are not pure substances but some form of extract from plant, fungi, yeast, or even animal origin. As I’ve said before time and time again, supplements that “work” (i.e., have some sort of biological effect) are drugs. They’re impure, adulterated drugs with highly variable potency because of their highly variable content of active ingredient. Obviously, supplements that don’t have such a biological effect are worthless (except for lining the pockets of supplement manufacturers). That’s why supplement manufacturers very much want consumers to believe that their supplements have a whole range of beneficial biological effects, and the DSHEA allows them to imply that, as long as they don’t do it too explicitly.

Martinez et al put the blame squarely where it belongs: On the DSHEA and another law. They also explain how supplement manufacturers get around even the weak prohibitions in the DSHEA:

Even without such direct statements, anticancer effects can be implied. For example, even though the manufacturers of Pill X cannot openly advertise that it prevents prostate cancer, they can create an advertisement that states that prostate cancer is a major health problem, that Pill X has a role to “support prostate health,” and that a particular study found that the compounds in Pill X reduced the growth of prostate cells in culture. Their website can then be accompanied by advertisements for Pill X and can contain links to testimonials that are free to expound the benefits of Pill X as experienced by real people. The absence of credible scientific evidence that taking Pill X confers anti-prostate cancer properties in men can be easily obscured by this constellation of claims that collectively suggest anticancer effects. As a result of limited regulatory authority, manufacturers who cannot overtly claim anticancer benefits of supplements without scientific proof are nonetheless free to imply those benefits in ways that make it difficult for the consumer to discern innuendo from scientific fact (82).

Indeed. Another recent review concluded that, with the possible exceptions of vitamin D and omega-3 fatty acids, there are no data to support the widespread use of dietary supplements in Westernized populations and that such supplements can even be harmful. Another recent study finds no effect from supplements on all-cause mortality and even found a negative effect from folic acid supplementation, consistent with yet another study. The bottom line is that, at present, it is quite probable that most supplements probably do more harm than good.

So why do so many people take supplements? Martinez et al also quite correctly point out:

Undoubtedly, use is driven by a common belief that supplements can improve health and protect against disease, and that at worst, they are harmless. However, the assumption that any dietary supplement is safe under all circumstances and in all quantities is no longer empirically reasonable. Believers in supplements are sometimes quick to discredit caution over supplement use, as they suggest that the tendency of mainstream science to ignore nonconventional evidence is tainted or that mainstream science is somehow corrupted by its link to a medical–industrial complex that seeks to protect profits rather than prevent disease.

Right on cue, our favorite quack apologist and supplement hawker, Joe Mercola, chimed in with an article entitled Over 60 Billion Doses a Year and Not ONE Death, But Still Not Safe? In it, Mercola in his usual frothing-at-the-mouth style (although not nearly as frothy as another favorite quack apologist Mike Adams) rants that a recent survey from the American Association of Poison Control Centers’ National Poison Data System reveals, there were zero deaths linked to nutritional supplements in 2010, amusingly citing the Orthomolecular Medicine News Service as its source. Orthomolecular medicine, you might recall, is a form of supplement quackery originally embraced by Linus Pauling when he concluded that high dose vitamin C was the cure for the common cold and cancer.

Never let it be said that Mercola isn’t good at intentionally confusing short term toxicity with long term effects in his eagerness to attack a straw man. He seems to think that when scientists point out that supplements can be hazardous that they are claiming that supplements will kill you fast when in reality most potential problems with supplements are long term health effects, although, I would point out, certain supplements can certainly cause serious problems more acutely. In any case, when Mercola asks, “Where are the bodies?” I’d answer that if a supplement increases the risk of a common cancer by 25%, that’s a lot of potential bodies. They just won’t be directly linked to supplements. Particularly amusing is Mercola’s outrage that the FDA is trying to impose the same limits on supplements as on aspartame, monosodium glutamate, and sodium nitrate.

What is infuriating Mercola and the supplement industry are draft guidelines from the FDA designed to assess new ingredients in supplements using safety standards similar to what are required for the approval of new food additives, as described in this recent New England Journal of Medicine commentary:

The proposed guidance clarifies the level of evidence the FDA would use to assess safety. Specifically, the safety of supplements would be evaluated according to three key factors: documented history of use (e.g., in foods or in supplements or herbal medicines sold outside the United States), formulation and proposed daily dose (e.g., more or less than was formerly consumed), and the recommended duration of use (e.g., intermittent or long-term). The FDA’s guidance provides a thoughtful framework for evaluating the safety of new ingredients (see table Required Safety Testing for New Dietary Ingredients Labeled for Intermittent Use.), and if implemented it would lead to substantial improvement in safety. For example, the FDA would require in vitro, animal, and tolerability testing for products that would be marketed for consumption at doses greater than those historically ingested.

In actuality, however, even these draft guidelines do not go far enough, and the supplement industry is vigorously opposing them, even though they strike me as an eminently reasonable strategy for trying to address at least one of the shortcomings of the DSHEA. After all, don’t supplement manufacturers themselves claim that their supplements are food, not medicine? Then why not require that new supplement ingredients without documented historical usage be subject to the same requirements for safety as any other food additive?

It’s important to remember that, in the end, supplements that have biological activity are functioning as drugs. As Martinez et al and a number of other studies strongly suggest, there is very little, if any, evidence that supplements improve health, at least in an already well-fed population, with a precious few possible exceptions that are far more narrow than anything CAM advocates or supplement manufacturers claim. Worse, at least as it stands right now, for most supplements, it is disturbingly likely that the harms probably outweigh the benefits for most people. This is one area where we probably do need more studies, but they need to be “strategically designed” studies, as Martinez et al put it, set up in light of existing evidence from previous studies that have been largely negative.

The nomenclatural confusion was created by the Dietary Supplement Health and Education Act of 1994 (DSHEA), which was termed “The Snake Oil Protection Act” by the New York Times. DSHEA, which was passed after a massive lobbying campaign by industry, arbitrarily designated herbals and other traditional medicinal products as dietary supplements. Herbals are used worldwide as medicines and in Europe some are available by prescription only.

The purpose of the Act was to prevent the Food and Drug Administration (FDA) from effectively regulating those products, and it succeeded brilliantly. Sales of dietary supplements rose from $4 billion annually in 1994 to $28 billion in 2007, and reports of severe adverse events caused by those products rose in parallel (1). Another consequence of DSHEA is that designating herbals as dietary supplements misleads consumers about their medicinal nature and conceals their potential for causing severe adverse effects.

The selling points for herbals are that as “natural” products they are safer and gentler than the powerful “foreign” chemicals in purified medications, and they possess unique qualities not found in conventional medications. Dr. Varro Tyler, an expert in the medicinal use of plants, termed those unfounded claims “paraherbalism”, and described herbals as “crude drugs of vegetable origin” (2). In reality, the active ingredients of plants are chemicals that are similar or identical to conventional medications, and many of the latter were first identified in plant extracts. It is no more “natural” to swallow dozens of chemicals in a plant extract than to ingest a single purified chemical – a drug is a drug. Before discussing CR’s advice about supplements, it is necessary to consider briefly basic differences between herbals and conventional medications.

The first issue is: what’s in the bottle? Safe and effective use of medications requires consistency in composition and biological activity. Prescription and over-the counter medications approved by the FDA are purified compounds whose activity is known. By contrast, the biological activities of herbals can’t be standardized because for the most part their active ingredient(s) have not been identified. Some herbals are standardized based on marker compounds, such as ginsenosides in ginseng. However, Consumer Reports (November 1995) found a 10-fold variation in the ginsenoside content of ginseng products, and aptly termed the variability “herbal roulette”. Moreover, many “all-natural” herbal remedies, especially those sold for sexual dysfunction or weight loss, are adulterated with undeclared prescription drugs. In a letter to supplement manufacturers, FDA commissioner Dr. Margaret Hamburg noted that in recent years the FDA has issued consumer warnings about nearly 300 products (3). She stated that “These tainted products can cause serious adverse events, including strokes, organ failure and death.”

A second concern is: what is the evidence that herbals are effective? Belief in the efficacy of herbals is based partly on their traditional use and partly on clinical trials funded by manufacturers. Reviews of those trials have pointed out their poor quality and very strong positive bias (4,5). Recent independently-funded trials of popular herbals, including echinacea, black cohosh, saw palmetto and ginkgo biloba, have been uniformly negative.

A third issue is the safety of herbals. Unlike clinical trials of purified medications, herbal trials have not included laboratory tests to detect damage to the liver and kidney, and until recently manufacturers were not required to report adverse effects to the FDA. Despite the lack of an effective reporting system, there are numerous reports of severe adverse effects caused by herbals, and the FDA recently estimated their annual frequency at 50,000 (6). Herbals may also cause adverse effects because of their interaction with conventional medications. St John’s wort decreases the levels of many common medications because it increases the activity of enzymes that inactivate them. The elderly are at particular risk because of chronic illnesses and their frequent use of prescription medications.

In summary, in the absence of sound evidence about the efficacy of herbals beyond a placebo effect, uncertainty about their activity and purity, and growing information about their adverse effects, their use should be discouraged.

There is a striking difference between CR’s critical, evidence-based evaluation of conventional medical treatments and health beliefs, and its soft standards concerning alternative therapies. An example of the former is a critique of conventional “health truths” in the January 2012 issue, in which the limitations of routine screening for prostate cancer were noted, as well as the lack of evidence for the health benefits and possible hazards of multivitamins.

In contrast, recommendations for considering the use of herbals and non-vitamin, non-mineral supplements are hedged by noting that “there is some evidence supporting their use” or that “small trials suggest benefit”. Some recent recommendations include black cohosh and soy for relief of menopausal symptoms, saw palmetto for benign prostate enlargement (February 2012), and glucosamine for arthritis. Those recommendations are based on industry-funded trials, whose deficiencies were noted above, and the negative findings of more rigorous independent trials were overlooked. Moreover, potential hazards, such as the association of black cohosh consumption with severe inflammation of the liver are overlooked.

In its recommendations for herbals to consider, CR states repeatedly that a mark of approval from the United States Pharmacopeia (USP) verifies “the quality, purity and potency of its raw ingredients or finished product”. That is the standard terminology USP uses for products that it analyzes and approves, but it is only partially accurate when applied to botanical products. The USP analysis uses chromatographic procedures to verify the source of the botanical extract, and the absence of contamination with microbial products and heavy metals (7). However, since the active ingredients of most botanicals have not been identified, analysis of marker compounds provides no information regarding the pharmacological activity or “potency” of the product. Moreover, the USP does not test for the presence of purified drugs, which are potentially dangerous contaminants.

Consumer Reports also promotes the use of other alternative therapies. The September 2011 issue contains an article entitled “Alternative Therapies. More than 45,000 readers tell us what helped”. In an online survey subscribers were asked to rate how well conventional and alternative therapies worked for 12 common health problems. For osteoarthritis, 46% of responders who used chiropractic felt the treatment helped a lot, as did 25% of those who used glucosamine/chondroitin. For back pain, 65% who used chiropractic and 41% who used acupuncture felt that those therapies helped a lot. An assessment of the evidence supporting those treatments was provided by the Natural Medicine Comprehensive Database (NMCD). The NMCD assessment of evidence, which is based on their review of published clinical trials, doesn’t take into account the poor methodological quality and strong positive bias of most of those trials (4,5). Glucosamine was rated by NMCD as “likely effective” for osteoarthritis, but an analysis of published trials revealed that all industry-supported trials were positive and all independently-funded trials were negative (8). Chiropractic and acupuncture were rated as “possibly effective” for back pain. There is little evidence for a specific effect of chiropractic manipulation, and recent evidence indicates that acupuncture for pain is a placebo treatment (9, 10). The article also contains testimonials to the dramatic benefits provided by chiropractic and acupuncture.

What significance should be attached to the responders’ belief that they received specific benefits from alternative treatments? Many health problems are self-limited, and placebos may be effective for relief of pain. In a clinical trial of glucosamine for osteoarthritis of the knee, 60% of patients who received a placebo pill met the criteria for a positive outcome, and glucosamine was no better than placebo (11). A recent study of patients with asthma provides another illustration of placebo effects (12 ). Patients received treatment with either an inhaler containing a bronchodilator, a placebo inhaler, sham acupuncture or no treatment. Patients in all three treatment groups reported equal subjective improvement compared to no treatment, but only patients who received the bronchodilator exhibited improvement in an objective test of lung function. Another problem with article is that conventional medications, such as “mainstream vitamins and minerals” and stress reduction, were included in the category of alternative therapies. Although the article does note that “our results do not take into account the power of the placebo effect”, the message conveyed by the survey is that some alternative therapies are effective. Moreover, the article provides information to assist readers to locate acupuncturists and chiropractors

The different standard used by CR Health Reports to evaluate conventional and alternative treatments is based, in part, on its choice of consultants. A list of some of the experts consulted, “health authorities and medical researchers”, is included in each issue. Most consultants are highly qualified academics and health professionals. However, in the April 2011 issue, which contains an article on popular nutritional supplements, one of the consultants listed is the editor of NMCD, whose shortcomings were noted above.

Another CR medical adviser is Joseph Mosquera, MD, who is the clinical director of an integrative medical program. The terminology used to describe belief-based medical practices has evolved from “alternative” to “complementary and alternative” to “integrative”. The agenda of integrative programs is to introduce safe and effective alternative therapies into education for health care professionals. I recently reviewed the poor quality of integrative curricula, and pointed out the lack of oversight of integrative programs by health profession schools (13).

The selection of alternative medicine advocates as consultants, rather than independent scientists and physicians, is a decision made by the editorial boards of CR and CR Reports on Health. That is a departure from CRs’ policy of avoiding bias and conflicts of interest, and from its mission to “empower consumers to protect themselves”. Empowering consumers to make informed decicisions about health care requires providing them with the soundest information available. The need for better consumer education was noted in a recent report from the United States Government Accountability Office that documented the prevalence of deceptive marketing practices and illegal health claims made for dietary supplements (14). As a respected source of information for consumers, CR should use the same high standard of evidence for evaluating alternative therapies that it employs for other medical treatments.

About the Author

Donald M. Marcus is an Emeritus Professor of Medicine and Immunology at Baylor College of Medicine in Houston. A graduate of Columbia University College of Physicians & Surgeons, he did his medical residency and postdoctoral training in Immunology at Columbia. He is a rheumatologist and formerly directed Rheumatology divisions at Albert Einstein College of Medicine and at Baylor. For the last 12-13 years he has taught medical students and physicians an evidence-based approach to complementary and alternative medicine (CAM), and published papers about CAM, especially dietary supplements.

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11. Clegg DO, Reda DJ, Harris CL, Klein MA, O’Dell JR, Hooper MM et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med 2006; 354:795-808
12. Wechsler ME, Kelley JM, Boyd IOE, Dutile S, Marigowda G, Kirsch I et al. Active albuterol or placebo, sham acupuncture, or no intervention in asthma. N Eng J Med 2011; 365:119-26.
13. Marcus DM, McCullough L. How good is the evidence in evidence-based integrative medicine? Acad Med. 2009; 84(9):1229-34.
14. Herbal Dietary Supplements. Examples of Deceptive or Questionable Marketing Practices and Potentially Dangerous Advice. United States Government Accountability Office. GAO-10-662T, May 2010

An “adverse event” is an undesirable outcome related to the provision of healthcare. It may be a natural consequence of the underlying illness, or it could be related to a treatment provided. The use of the term “event” is deliberate, as it does not imply a cause: it is simply associated with an intervention. The term “adverse reaction,” or more specifically “adverse drug reaction,” is used where a causal relationship is strongly suspected. Not all adverse events can be be causally linked to health interventions. Consequently, many adverse events associated with drug treatments can only be considered “suspected” adverse drug reactions until more information emerges to suggest the relationship is likely to be true.

Correlation fallacies can be hard to identify, even for health professionals. You take a drug (or, say, are given a vaccine). Soon after, some event occurs. Was the event caused by the treatment? It’s one of the most common questions I receive: ”Does drug ‘X’ cause reaction ‘Y’?” We know correlation doesn’t equal causation. But we can do better than dismissing the relationship as anecdotal, as it could be real. Consider an adverse event that is a believed to be related to drug therapy:

• First, is the event an extension of the drug’s pharmacology? Is it predictable, based on how the drug works? For example, narcotics predictably cause constipation and cognitive impairment. Oral antibiotics cause diarrhea because they kill the normal flora in our colon.
• Secondly, what was observed in clinical trials? The product monograph or prescribing information usually summarizes which adverse events were reported in trials, and which were more frequently observed than in the placebo group.

Neither of the two approaches is comprehensive. If the suspected event is rare, it may not have shown up simply by chance alone, in the clinical trial. Or the event may develop slowly: clinical trials have a fixed duration, while treatments in the real world can last decades. The patient population in clinical trials is usually healthier and on fewer other medications than those in the real world. So to truly understand the adverse event profile, we need to look at real world data. We could turn to epidemiological studies that evaluate safety in real-world settings, often using massive treatment databases. While not as robust as data from a randomized controlled trial, and prone to misuse,  epidemiological studies can answer questions about vaccine safety or identify subtle effects of drugs on common events, like heart attacks.

If the event in question doesn’t show up in any other data source, but is suspicious, it might be appropriate to submit a report to the manufacturer or to the national drug regulator. Importantly, this is a suspected reaction — we cannot be certain the event was caused by a drug based on a single observation. But multiple reports, sent independently, could “signal” the need for more investigation. Consequently, countries with robust regulatory systems have all established systems for collecting spontaneous reports of harms. Systems generally include:

• mandatory reporting from drug manufacturers of any adverse event reported to the company
• optional or mandatory reporting from health professionals who become aware of possible adverse events
• the option for consumers to report harms directly to regulators (bypassing manufacturers or health professionals)
• collaboration with other countries to share information on adverse events that are collected.

There are four essential elements to any adverse event report:

• An identifiable patient: there must be a specific patient known to be involved, and adequate information is necessary (gender, age, etc.).
• An identifiable reporter.
• A suspected drug: the drug should be known. If a patient is on multiple drugs, they all need to be described in the report.
• A suspected adverse event or fatal outcome: specific signs and symptoms are required, and ideally a diagnosis as well (e.g.,”rash” isn’t specific enough to compare between reports).

Multiple reports are typically required to generate the safety “signal”, a flag that an association merits further investigation. The FDA compiles all adverse event reports it collects in the Adverse Event Reporting System (AERS), and continually analyzes that database, publishing possible signals that it has identified. While consumers and health professionals can submit reports to the FDA directly, the overwhelming majority of adverse events are reported by pharmaceutical manufacturers, who are required by law to forward all adverse events they identify. If an event described is serious and not already listed in the prescribing information, it must be forwarded to the FDA within 15 days. Here are the statistics from its Adverse Events Reporting System (AERS):

The blue bars are direct reports, submitted by health professionals or the public — about 4% of the total submitted in 2010. The remainder are submitted by manufacturers. Even massive numbers like these may not be sufficient to identify potential signals of adverse events related to treatments, so countries collaborate and share information: a bigger net can catch more safety signals, it seems. The Uppsala Monitoring Centre is an international collaboration, combining reports submitted by over 100 countries. It has amassed a database of over 7 million reports. Adverse event databases are great resources for identifying safety signals — albeit with some significant limitations.

The Trouble with (V)AERS

The misuse of vaccine-related adverse event reports — called VAERS, for Vaccine Adverse Event Reporting System — is a common tactic of antivaccine groups who believe that vaccines are unsafe and cause significant harms. And a database of suspected harms is a gold mine to those seeking anecdotes. Antivaccine groups have been known to mine the VAERS database, and draw causal relationships where none have been established.

There is no question that adverse effect databases can serve as a valuable resource as part of an overall program to monitor the safety and efficacy of a drug or vaccine. However, in isolation, these databases have limited utility. Patterns or “signals” are recurrent events observed in the data. They are hypothesis-generating — not hypothesis-answering. Most importantly, these databases cannot estimate the incidence of any adverse event. In order to estimate the incidence of an event, we need to know how many times it has occurred in a specified population size: the denominator, which is the total number of patients that have taken the drug (or vaccine, as the case may be). No denominator, no incidence. AERS cannot provide that information, given reporting is spontaneous, incomplete, and the size of the population taking the drug isn’t known. The FDA makes this very, very clear:

AERS data do have limitations. First, there is no certainty that the reported event was actually due to the product. FDA does not require that a causal relationship between a product and event be proven, and reports do not always contain enough detail to properly evaluate an event. Further, FDA does not receive all adverse event reports that occur with a product. Many factors can influence whether or not an event will be reported, such as the time a product has been marketed and publicity about an event. Therefore, AERS cannot be used to calculate the incidence of an adverse event in the U.S. population. [emphasis added]

The old adage that garbage in = garbage out holds true with adverse event databases. The quality of reporting is as important as, if not more important than, the quantity of these reports. Low quality reports, with incomplete data have the potential to increase the challenge of finding true safety signals. Trends in AERS and VAERS reports may also be subject to external pressures unrelated to drug effects. Relationships have been established between H1N1 media stories and VAERS reports. Vaccine litigation can do the same thing. Neither are real, but you need to look beyond the databases to answer the question. It would be interesting to see if some of the current medical-legal drug controversies (e.g., oral contraceptives, antipsychotics, and antidepressants) also have identifiable litigation-related trends in AERS databases.

The Power of Nocebo

Are all reported side effects real effects? Probably not. Any double-blind clinical trial will describe the side effects reported with both the active treatment, and the placebo. And adverse events from placebos can be so significant that they lead to treatment discontinuation. A systematic review of trials in patients with fibromyalgia noted that 67% of patients reported adverse events in the placebo arms, and 10% discontinued “treatment” with the placebo due to adverse effects. In a study of allergy treatments, 27% of participants reported allergic symptoms to a placebo challenge. And in a study that compared ASA (aspirin) versus placebo, describing potential adverse effects of therapy led to a “sixfold increase in the number of subjects withdrawing from the study because of subjective, minor, gastrointestinal symptoms” compared to study sites that did not provide that caution.

The recognition of nocebo effects is another consideration when evaluating individual adverse event reports.

Free the data!

While collecting and analyzing adverse event reports has been standard practice since the thalidomide disaster, the data only became publicly available more recently. Several years ago, the Canadian Broadcasting Corporation (CBC) used access-to-information laws to obtain access to Health Canada’s entire adverse event database, and posted the data online. Health Canada subsequently made the data available directly.  The FDA makes similar data available, which you can query directly. But given the limitations described above, the utility of these databases to the public or health professionals isn’t clear.

It seems clear to a new company, adverseevents.com, which aims to make AERS data more easily accessible, and to make money while doing so as the CMAJ described last week. Brian Overstreet, CEO, made the following comments:

We live in an information age, and there is an overwhelming pool of potential information for consumers to look at online. What’s lacking is a real statistical overview. We can come in and say, listen it’s nice that 200 people on this discussion board say they got an upset stomach, but we have 50 000 case reports, and from those we know 27% have an upset stomach. Having hard data to back up the real world perception I think is very, very valuable.

The FDA, and even they don’t know for sure, but they estimate maybe 10% of the serious adverse events are reported. But as much as we’re talking about a limited data set, three million case reports in the last seven years, it’s not a small data set. It’s a pretty robust data set. The data’s never going to be perfect, but it’s better than nothing, and so long as we’re treating it properly, the end result should be valuable.

The obvious problem with this approach, as I’ve pointed out above, is that it ignores the significant limitations of the data itself. You cannot estimate incidence without a denominator. And there is no denominator in the AERS data. These data limitations don’t stop the company from comparing within classes of drugs based on reported events, or even identifying which drugs are most likely to be associated with death.

Another group that recently announced a query service for adverse events reports is headed by Dr. David Healy, psychiatrist and author of the book Pharmageddon. He has launched an independent adverse event collection site, Rxrisk.org, which states:

There comes a point where, even if the clinical trial data says otherwise, it is just not reasonable to say the problem can’t be happening in at least some people. You and your healthcare team have been handed a megaphone!

It appears that Rxrisk.org will both analyze FDA-reported adverse events, as well as collect reports directly, and facilitate their submission. In an interview, Healy made the following comment:

People need to wake up and stop thinking that clinical trials have provided all the answers. We need to get back to believing the evidence of our own eyes. The key thing is to get the data. There isn’t anyone else getting data like this.

Given the dangers of drawing conclusions from spontaneous reports, and considering how the VAERS databases have been misused to make erroneous inferences about vaccine safety, I’m somewhat skeptical of what rxrisk.org and adverseeevents.com will contribute to our understanding of drug safety. The sites are not yet fully operational, so this may be a topic I’ll revisit in a future post.

Improving our drug safety monitoring systems

We all share the goal of wanting to understand the true risks of drug treatments. Part of supporting informed evaluations of risk and benefit means regulators must continuously monitor the real-world safety profile of licensed drugs. Adverse event databases perform a critical role in identifying possible safety signals and generating hypotheses that require additional analysis. The significant challenge is to differentiate between the useful signals and the noise, and recognize biases in our observations and in the way we collect this data. Otherwise we may well assign causality where none may exist — another sort of poor outcome.

Adverse effect reporting systems are designed to enhance patient safety. They are one tool, unquestionably useful, but limited in utility. If we don’t keep these limitations in mind, we run the risk of worsening, not improving, our understanding of a treatment’s risk and benefit.

What Is Hypnosis?

Any meaningful discussion of hypnosis, or any other phenomenon, needs to start with a specific, and hopefully operational, definition.  If we cannot define hypnosis then it becomes impossible to meaningfully discuss it. The problem of definition plagues the science dealing with many so-called alternative therapies, such as acupuncture.  Good science requires controlling for specific variables, so that we can determine which variables are having what effects. If we don’t know which variables are part of the operational definition of a specific therapy, then we cannot conduct proper studies or interpret their results.

For example, with acupuncture, in my opinion the only meaningful definition of this procedure is the placing of thin needles into specific acupuncture points in order to elicit a specific response. Research has shown, however, that acupuncture points do not exist, that placing needles at specific points is not associated with a specific outcome, and even that sticking needles through the skin (as opposed to just poking the skin superficially) does not correlate with outcome. When these variables are isolated they do not appear to contribute anything to efficacy, therefore one might conclude that acupuncture does not work. Research into acupuncture, however, often does not adequately isolate these variables from the therapeutic ritual that surrounds acupuncture, or even mixes in other modalities, such as electrical stimulation.

Psychologically-based therapies all suffer from this potential failing as well. It is difficult to separate the variables that are specific to a treatment from the non-specific elements of the therapeutic interaction.

What, then, are the variables specific to hypnosis that make it an identifiable intervention? This is not clear, but we can start with a definition of hypnosis based upon our current understanding. Hypnosis, first of all, is not what happens on stage for the purpose of entertainment. It is not about making people act like a chicken. It is also not a deep sleep or trance-like state. Hypnosis, however, is believed to be a specific state of consciousness. We experience different states of consciousness all the time, defined by differences in alertness and focus of attention. Hypnosis, rather than being a sleep-like state, is actually a state of heightened alertness. Attention, however, is focused (usually on the hypnotist or something they are using as a focus of attention). In this state subjects are more responsive to social cues and suggestion.

The above description of hypnosis is fairly superficial, and is still a matter of ongoing debate. There are conflicts between the conceptual definition of hypnosis (what we think is going on in the brain) and the operational definition (how we define it experimentally). Some researchers suggest that the operational definition is simply increased suggestibility following a hypnotic induction procedure. Even this stripped down definition has problems as it is not clear if hypnosis depth scales are just measuring baseline suggestibility, rather than a hypnosis effect.

My understanding of the current state of the research is that the hypnotic induction procedure may place subjects in a state in which they are focusing their conscious attention and are more receptive to unconscious processing of information (suggestibility). Beyond this there are many theories as to what is going on in the brain, but at present we simply do not really know and much more research is needed. There is no consensus as to the theoretical model of hypnosis. This makes clinical research into hypnosis difficult.

Hypnosis as Therapy

Regardless of the conceptual definition of hypnosis, if we have a standardized operational definition then we can study its effects. Systematic reviews of hypnosis for specific indications, however, generally observe heterogeneity of operational definition of hypnosis across trials. In other words — there often is no consistent operational definition of hypnosis and this makes it difficult to interpret study results. This is another way of saying that clinical research often does not adequately control for variables that allow us to isolate something that can meaningfully be called “hypnosis.”

This is all another way of saying that effects seen from hypnosis may all be either placebo effects or non-specific effects from the therapeutic interaction, rather than a specific response to hypnosis itself.

A systematic review of hypnosis for fibromyalgia pain, for example, found that:

The significant effect on pain at final treatment was associated with low methodological and low treatment quality.

CONCLUSION: Further studies with better treatment quality and adequate methodological quality assessing all key domains of FMS are necessary to clarify the efficacy of H/GI in FMS.

Studies used variable definitions of hypnosis and control of what exactly was being delivered, and poor study quality correlated with positive outcome — a trend that always calls into question whether or not there is a real effect present.

Other systematic reviews of hypnosis for pain control generally find positive effects, but they do not always carefully assess for methodological quality (such as for cancer pain). A systematic review of hypnosis for labor pain also found positive effects, but also cited methodological limitations in the research.

The major limitation of much of this research is that it does not adequately control for the effects of relaxation, cognitive therapy, expectation, or the introduction of a novel therapeutic intervention — all phenomena that may “come along for the ride” with hypnotherapy but not be specific to hypnotherapy. In other words — is hypnotherapy a necessary component of a positive therapeutic effect or is it an unnecessary ritual by which other non-specific elements have an effect? Some researchers are trying to tease apart these variables, but that constitutes a minority of the clinical research on hypnotherapy.

Conclusion

My personal current summary of the clinical research is that there is a suggestion of a positive effect from the specific operational elements of hypnosis (specifically increased suggestibility) for the treatment of subjective symptoms, like pain and nausea, that are amenable to suggestibility. However, the research has not yet adequately isolated this variable and therefore more research of better methodological quality is necessary to definitively answer this question. Until then hypnotherapy will remain controversial.

The more basic question as to what hypnosis is also is in an early stage of research, although there do seem to be some promising conceptual theories. The use of fMRI and other techniques may help define hypnosis from a neuroanatomical perspective, and this may further aid in understanding what hypnosis actually is.

Meanwhile, I find it counterproductive to lump hypnosis in with the broad and poorly defined category of “alternative” therapies. A recent article on hypnotherapy, for example, contained this quote from a practitioner:

“You can think of it in the same general healing family as acupuncture, massage [or] Chinese herbs,” he said. “All of these are kind of nonmainstream or alternative or holistic treatments. But they are gaining much more respect and popularity every year in our country. These are things they’ve been doing in China or India for thousands of years.”

You can see how this approach causes only confusion. Hypnotherapy has not been used in China or India for thousands of years, and has absolutely nothing conceptually in common with any of the modalities mentioned. The only possible connection among these various treatments that would put them into a common “alternative” group is the lack of scientific support or the confusion of placebo effects for specific effects. This is exactly what I meant by the “ghettoizing” of hypnotherapy.

It would be unfortunate for this to happen. I would rather see hard scientific research to better define hypnosis and its therapeutic potential.

NUHS. The article was co-authored by several chiropractors on the faculty of the National University of Health Sciences, a school noted for integrating quackery with medicine. The “sciences” this school teaches are listed at the top of its website: chiropractic medicine, naturopathic medicine, oriental medicine, acupuncture, biomedical science, and massage therapy. The only one of those that even sounds like science, “biomedical science,” offers a bachelor of science degree with an integrative medicine focus and with no required core courses whatsoever!

Their doctor of chiropractic degree program says:

National University prepares students to become first-contact, primary care physicians fully qualified to diagnose, treat and manage a wide range of conditions.

Background. The authors say proposals to classify chiropractors as primary care physicians date back to at least 1967, with the Comprehensive Health Planning Councils. Arguably, the concept of chiropractors providing comprehensive health care dates back to the origin of chiropractic, since its founder asserted that all human disease was attributable to subluxations, 95% in the spine and 5% elsewhere. On the other hand, chiropractors used to claim they didn’t diagnose or treat illness, but only kept the spine in proper alignment so that the vitalistic force they called “Innate” could take care of anything and everything. In essence, doesn’t their aspiration to become “family doctors” amount to an admission that chiropractic is not the panacea they once held it to be? Doesn’t their wish to branch out demonstrate the failure of their discipline?

Their Arguments. They argue that more primary care providers are needed, and that chiropractors can fill the gap. They argue that using chiropractors as gatekeepers will reduce costs.

When chiropractic physicians functioned as primary care gatekeepers, pharmaceutical costs fell by 58.1 percent and hospital admissions by 43 percent. These are statistics that clearly support the value of the chiropractic physician in the primary care, gatekeeper position.

These statistics, even if correct, do not support the value of the chiropractor as gatekeeper. Cheaper is not better if it reduces quality of care. Of course pharmaceutical costs went down, because chiropractors can’t prescribe pharmaceuticals and they typically discourage patients from using them. They discourage surgery and conventional medical care, so it’s not surprising that hospital admissions fell; but maybe some of those patients would have been better off in the hospital. And I would guess that vaccination costs dropped too, since only around half of chiropractors support vaccination. We need to know the health outcomes for those patients, not just how much money was saved. Parents who belong to faith healing cults and never take their children to a doctor can cut medical costs to zero, but sometimes the children die.

Apart from the question of costs, the ability of chiropractors to function effectively as gatekeepers has not been tested in any formal study. It is questionable, to say the least. There is anecdotal evidence that occasionally a chiropractor makes a diagnosis that MDs have missed and that many chiropractors refer appropriately, but there is at least as much anecdotal evidence that chiropractors have missed diagnoses that would be obvious to any MD, and that they have failed to send patients to the emergency room for medical emergencies such as classic heart attack symptoms or fevers in very young infants.

They recognize that not all chiropractors are willing or able to carry out their vision:

Among the challenges is the diversity of our colleagues—those wanting to participate in primary care who order technical diagnostic procedures and clinical laboratory tests versus those who want to remain subluxation based. There are those who want to treat the whole person versus those who want to treat only musculoskeletal conditions. There are those of us who want to use treatment modalities beyond the adjustment, as well as those who feel we should adjust only the spine.

Managing Chronic Disease

“Conservative primary care physician” is language intended to clarify that as chiropractic physicians we do not address the complex primary care disease states that require pharmaceutical intervention and management.

Unfortunately, many do. I am increasingly hearing about chiropractors who profess to cure diabetes.  They call themselves “doctors” and many of their patients don’t realize they are seeing chiropractors.

Chiropractors aspire to being part of a health care team, managing musculoskeletal problems and “co-managing” chronic diseases by counseling on lifestyle, diet, and exercise. They want to manage psychosocial issues such as anxiety and depression, and they want to use preventive management strategies to reduce the incidence of cancer and dementia.  They want to.  But that doesn’t mean they can.

A Primer on the History and Physical. After saying in part 1 that chiropractors should provide primary care, they proceed in part 2 to a primer on how to take a history. The fact that they feel a need to explain this implies that chiropractors don’t already understand the basic principles. They proceed to explain how to ask about chief complaint, history of present illness, past medical history, family history, social history, and review of systems. They even feel a need to explicitly remind chiropractors to ask if the patient smokes!

Even their attempt to instruct chiropractors is flawed. For instance, they recommend simple lab tests, but their recommendations for sedimentation rates and CRP testing are not evidence-based and do not correspond to standard medical practice.

In part 3, they describe an office visit and comprehensive physical exam in great detail, with many recommendations that are non-standard and not evidence-based:

• Routine pulse oximeter readings on every patient. (This may be routine in the ER, but it is not and should not be a routine part of every visit to a doctor’s office.)
• If any vital signs are abnormal, instead of taking prompt and appropriate action, they recommend that “they should be tracked on a regular basis to determine if a specialist consultation and/or further medical intervention is needed.”
• For trauma patients, they recommend assessing the patient’s short and long term memory and considering a mini-mental status test. (For most trauma patients this would be a waste of time.)
• As part of the chest exam, they recommend testing tactile fremitus. Abnormal tactile fremitus is a sign of lung consolidation in patients with pneumonia. It is only appropriate as part of a directed physical to pin down a suspected diagnosis, and even then it is not a particularly useful test. It’s one of those things doctors learned in medical school but rarely if ever use in practice because there are far better ways to make the diagnosis.
• “The role of testing for H. pylori infection in GERD (gastrointestinal reflux disease) remains controversial.” No, it doesn’t. There’s no controversy: there’s a clear consensus that such testing is not indicated. Some patients can be treated on the basis of symptoms alone; others will need endoscopy. H. pylori testing is done for suspected ulcers, not for GERD.

What really surprised me was their extensive coverage of the musculoskeletal exam. This is their particular area of expertise; surely chiropractors don’t need to be reminded about how to evaluate joint motion, muscle strength, and tender points. They ask “Is there any indication that the patient would be at increased risk for spinal manipulation of the neck?” It seems they recognize that neck manipulation can precipitate a stroke; unfortunately, there is no reliable way to rule out risk, and implying that chiropractors can do so is misleading and dangerous.

This whole exercise struck me as silly, condescending, and embarrassing. If chiropractors were already qualified to be primary care providers, they wouldn’t need to be given this information. If they are not qualified, a simplistic tutorial like this isn’t enough to educate them.

Legislation and Other Developments. Legislation has been proposed to expand the scope of chiropractic and even to authorize limited prescribing privileges. Government programs and insurance companies are considering expanding reimbursement policies. In some places chiropractors are authorized to do sports physicals as well as drug testing and DOT physicals for commercial drivers licenses. National University is even offering what they call a family practice residency.

Other Non-MDs Do It. It could be argued that other non-MD providers carry out primary care and gatekeeper functions. Physician assistants are one example whose training equips them to do the job well. My main concerns about chiropractors assuming these functions are:

• Their thought processes and clinical judgment have developed in the context of a discipline that was originally based on erroneous ideas and that is still lacking in scientific rigor. (These authors still speak of the “subluxation.”)
• Their training has not exposed them to seriously ill, hospitalized patients, which I think is essential to developing judgment about situations requiring emergency care or referral.
• Many chiropractors espouse nonsensical tests and treatments. Just one example: according to an American Chiropractic Association survey, an appalling 38% of US chiropractors use applied kinesiology, one of the most ridiculous travesties in all of alternative medicine.
• Patients under the care of chiropractors are less likely to get vaccinations; only around half of chiropractors recommend them.
• Chiropractors should not be treating children, but many do so.

Bottom line: Some chiropractors are family doctor wannabes, but they are not equipped to fill that role.

Fascinating. That’s an 88.6 percent unreliability rate for landmark, gold-standard science. Imagine how bad it is in the stuff that is only peer-reviewed and isn’t even theoretically replicable, like evolutionary biology. Keep that figure in mind the next time some secularist is claiming that we should structure society around scientific technocracy; they are arguing for the foundation of society upon something that has a reliability rate of 11 percent.

Now, I’ve noted previously that atheists often attempt to compare ideal science with real theology and noted that in a fair comparison, ideal theology trumps ideal science. But as we gather more evidence about the true reliability of science, it is becoming increasingly obvious that real theology also trumps real science. The selling point of science is supposed to be its replicability… so what is the value of science that cannot be repeated?

No, a problem with science as it is carried out by scientists in the real world doesn’t mean that religion is true or that a crank like Vox is somehow the “real” intellectual defender of science. Later, Vox doubles down on his misunderstanding by trying to argue that the problem in this article means that science is not, in fact, “self-correcting.” This is, of course, nonsense in that the very article Vox is touting is an example of science trying to correct itself. Be that at it may, none of this is surprising, given that Vox has demonstrated considerable crank magnetism, being antivaccine, anti-evolution, an anthropogenic global warming denialist, and just in general anti-science, but he’s not alone. Quackery supporters of all stripes are jumping on the bandwagon to imply that this study somehow “proves” that the scientific basis of medicine is invalid. A writer at Mike Adams’ wretched hive of scum and quackery, NaturalNews.com, crows:

Begley says he cannot publish the names of the studies whose findings are false. But since it is now apparent that the vast majority of them are invalid, it only follows that the vast majority of modern approaches to cancer treatment are also invalid.

But does this study show this? I must admit that it was a topic of conversation at the recent AACR meeting, given that the article was published shortly before the meeting. It’s also been a topic of e-mail conversations and debates at my very own institution. But do the findings reported in this article mean that the scientific basis of cancer treatment is so off-base that quackery of the sort championed by Mike Adams is a viable alternative or that science-based medicine is irrevocably broken?

Not so fast there, pardner…

A systemic problem with preclinical research? Maybe. Maybe not.

One of the most difficult aspects of science to convey to the general public about science-based medicine (and science in general) is just how messy it is. Scientists know that early reports in the peer-reviewed literature are by their very nature tentative and have a high probability of ultimately being found to be incorrect. Unfortunately, that is not science as it is imbibed by the public. Fed by too-trite tales of simple linear progressions from observation to theory to observation to better theory taught in school, as well as media portrayals of scientists as finding answers fast, most people seem to think that science is staid, predictable, and able to generate results virtually on demand. This sort of impression is fed even by shows that I kind of like for their ability to excite people about science, for instance CSI: Crime Scene Investigation and all of its offspring and many imitators. These shows portray beautiful people wearing beautiful pristine lab coats back lit in beautiful labs using perfectly styled multicolored Eppendorf tubes doing various assays and getting answers in minutes that normally take hours, days, or sometimes weeks. Often these assays are all done over a backing soundtrack consisting of classic rock or newer (but still relatively safe) “alternative” rock. And that’s just for applied science, in which no truly new ground is broken and no new discoveries are made.

Real scientists know that cutting edge (or even not-so-cutting edge) scientific and medical research isn’t like that at all. It’s tentative. It might well be wrong. It might even on occasion be spectacularly wrong. But even results that are later found to be wrong are potentially valuable.

Sometimes moviemakers and TV producers get it close to right in showing how difficult science is. For example the HBO movie Something The Lord Made showed just how difficult it could be to take a scientifically plausible hypothesis and turn it into a treatment. In most movies, TV shows, and popular writings, the retrospectoscope makes it seem as though what we know now flowed obviously from the observations of scientific giants. Meanwhile, the news media pounces on each new press release describing new studies as though each was a breakthrough, even though the vast majority of new studies, even seemingly interesting ones, fade into obscurity, to be replaced by the next new “breakthrough.”

In the real world of science, however, things are, as I said, messy. What amazes me is how two scientists, one of whom I respect, can fall prey to amazement when they point out just how messy science is. I’m referring to a commentary that appeared in Nature three weeks ago by C. Glenn Begley, a consultant for Amgen, and Lee M. Ellis, a cancer surgeon at the University of Texas M.D. Anderson Cancer Center. The article was entitled, unimaginatively enough, Drug development: Raise standards for preclinical cancer research. This article is simultaneously an indictment of preclinical research for cancer and a proposal for working to correct the problems identified. It is also simultaneously disturbing, reassuring, and, unfortunately, more than a little misguided.

Before I get into the article, let me just expound a bit (or pontificate or bloviate, depending on what you think of my opinionated writing) about preclinical research. Preclinical research is, by definition, preclinical. It’s the groundwork, the preliminary research, that needs to be done to determine the plausibility and feasibility of a new treatment before testing it out in humans. As such, preclinical research encompasses basic research and translational research and can include biochemical, cell culture, and animal experiments. Depending on the nature of the problem and proposed treatment, it could also include chemistry, engineering, and surgical research.

Now here’s the pontification and bloviation. These days, everybody touts “translational” research, meaning research that is designed to have its results translated into human treatments. It’s darned near impossible these days to get a pure basic science project funded by the NIH; there has to be a translational angle. Often this leads basic scientists to find rather—shall we say?—creative ways of selling their research as potentially having a rapid clinical application, even though they know and reviewers know that such an application could be a decade away. Indeed, if we are to believe John Ioannidis, the median time from idea to completion of large scale clinical trials needed to approve a new treatment based on that idea is on the order of one to two decades. Moreover, as I’ve said many times before, translational research will grind to a halt if there isn’t a robust pipeline of basic science research to provide hypotheses and new biological understandings to test in more “practical” trials. A robust pipeline is necessary because the vast majority of discoveries that look promising in terms of resulting in a therapy will not pan out. That is the nature of science, after all. Many leads are identified; few end up being a treatment.

Not surprisingly, this nature of science seems to be what concerns Begley and Ellis. They begin by pointing out:

Sadly, clinical trials in oncology have the highest failure rate compared with other therapeutic areas. Given the high unmet need in oncology, it is understandable that barriers to clinical development may be lower than for other disease areas, and a larger number of drugs with suboptimal preclinical validation will enter oncology trials. However, this low success rate is not sustainable or acceptable, and investigators must reassess their approach to translating discovery research into greater clinical success and impact.

Of course, some of the reason that clinical trials in oncology have a high failure rate is no doubt due to the high difficulty of the disease (actually many diseases) being tackled. As I’ve pointed out time and time again, cancer is very, very complicated and very, very hard. Given that challenge, as frustrating as it is, it is probably not surprising that only around 5% of agents found to have anticancer activity in preclinical experiments go on to demonstrate sufficient efficacy in phase III clinical trials to earn licensing for sale and use. That is compared to approximately 20% for cardiovascular disease. Of course, cardiovascular drugs are targeted at cells that are nowhere near as messed up as cancer cells, and another study cited by Begley and Ellis suggests that between 20-25% of important preclinical results can’t be reproduced in pharmaceutical company laboratories with sufficient rigor to go forward. Even so, being scientists, we want to improve the process. To improve the process, however, we need to know where the process fails.

To try to do this, Begley and Ellis looked at 53 “landmark” publications in cancer. Begley used to be head of global cancer research at Amgen and knows what it takes to get a drug from idea to market. What it takes first is replication. Basically, Begley’s team would scour the scientific literature for interesting and promising results and then try to replicate them in such a way that their results could serve as a basis for developing drugs based on them. The idea was to identify new molecular targets for cancer and then figure out ways to make drugs to target them. This is what he reported:

Over the past decade, before pursuing a particular line of research, scientists (including C.G.B.) in the haematology and oncology department at the biotechnology firm Amgen in Thousand Oaks, California, tried to confirm published findings related to that work. Fifty-three papers were deemed ‘landmark’ studies (see ‘Reproducibility of research findings’). It was acknowledged from the outset that some of the data might not hold up, because papers were deliberately selected that described something completely new, such as fresh approaches to targeting cancers or alternative clinical uses for existing therapeutics. Nevertheless, scientific findings were confirmed in only 6 (11%) cases. Even knowing the limitations of preclinical research, this was a shocking result.

Here’s the part that I found to be profoundly misguided. Begley and Ellis basically admit that these are “landmark papers”; i.e., that they were highly novel. Presumably these papers would have been considered at the time of their publication to be “cutting edge” research, very likely published in high impact journals such as Nature, Cell, Science, Cancer Research, and the like. Unfortunately, although I looked, I didn’t see a list of the 53 “landmark papers—not even in an online supplement. Nor was the method of how these papers were analyzed described in much detail—not even in an online supplement. The irony inherent in a paper that rails against the irreproducibility of preclinical cancer research but does not itself provide the data upon which its authors based its conclusions in sufficient detail for the reader to determine for himself whether the conclusions flow from the data is left for SBM readers to assess for themselves. Similarly misguided, as was pointed out in the online comments, were the authors’ stated assumption that “the claims in a preclinical study can be taken at face value — that although there might be some errors in detail, the main message of the paper can be relied on and the data will, for the most part, stand the test of time” and their amazement that “this is not always the case.” If the authors’ assumptions were true, attempts to replicate scientific results would be less important than they are.

Be that as it may, what the authors are studying, however they studied it and whatever the 53 studies they examined were, is essentially frontier science. Given that, it strikes me as rather strange that they are so amazed that much of the science at the very frontiers turns out not to be correct when tested further. We in science understand the difference between settled textbook science and the sort of frontier science that makes it into journals like Science. Indeed, we often lament that the very highest tier journals, such as Nature, Science, and Cell, tend to be too enamored of publishing what seems to be “sexy science,” exciting or counterintuitive results that really grab the attention of scientists — in other words “cutting edge” or frontier science. Such journals seem to pride themselves on publishing primarily such work (which is one reason why they are so widely read and cited), while more solid, less “sexy” results seem to end up in second-tier journals.

This leads to a paradox: the science that is published in the highest profile, most prestigious journals is almost by definition the most tentative science. Given that, it is surprising how much of what is published in such journals actually does stand the test of time, but it should not be surprising that much of it does not. However, the very prestige of such journals gives such research seemingly more authority than research published in less prestigious journals. It is often said that one Nature, Science, or Cell paper is worth five or even ten papers in more pedestrian, middle-of-the-road journals when it comes to improving a scientist’s CV (and chance of a good job or promotion). Perhaps that is because publications in such journals are viewed as an indication that the work a scientist is doing is on the cutting edge. That perception, built up over time, is likely the major reason that it is very, very difficult to get a paper accepted and published in Science, Nature, or Cell. The vast majority of submissions are rejected, many without even being sent out for peer review, because an editorial decision is made that they are not “interesting” enough (something that happened to me once). In other words, the editors of such journals are actively looking for science that challenges the existing paradigm. However, scientists understand that papers published in the most cutting edge journals are tentative. They’re interested in the papers because such work is the most likely to advance the frontiers of science.

In fact, they’re interested in such papers for the very same reason that Begley and his group at Amgen were interested in them. Begley was the head of a major research division of a major pharmaceutical company. What does that mean? It means that it was his job to find new molecular targets for cancer and to develop drugs to target them. And it was his job to do all this and beat his competitors to the market with effective new drugs based on these discoveries. No wonder his group scoured high impact journals for cutting edge studies that appeared to have identified promising molecular targets! Then he had a veritable army of scientists, about 100 of them in the Amgen replication team according to this news report, who were ready to pounce on any published study that suggested a molecular target the company deemed promising.

Here’s another aspect of the study that needs to be addressed. As I read the study, a thought kept popping into my fragile eggshell mind. Remember Reynold Spector? He’s the guy whom both Mark Crislip and I jumped on for a particularly bad criticism of science-based medicine and its alleged lack of progress that Spector called Seven Deadly Medical Hypotheses. As both Mark and I pointed out, nearly all of these hypotheses were really not particularly deadly, and, indeed, most of them weren’t even hypotheses. What Dr. Spector shares in common with Dr. Begley is a background in pharma, and the similarities in the way they think are obvious to all. For instance, I castigated Spector for throwing around the term “pseudoscience” to describe studies that in his estimation do not reach the level of evidence necessary for FDA approval of a drug. That is a very specific set of requirements for a very specific problem: developing a drug from first scientific principles and then demonstrating that it is efficacious for the intended indication as well as safe. I got the impression from his articles that Dr. Spector views any study that doesn’t reach FDA-level standards for drug approval to be pseudoscience — or, at the very least, crap. I get the same impression from Begley. For example, here’s a passage from his article:

Of course, the validation attempts may have failed because of technical differences or difficulties, despite efforts to ensure that this was not the case. Additional models were also used in the validation, because to drive a drug-development programme it is essential that findings are sufficiently robust and applicable beyond the one narrow experimental model that may have been enough for publication.

Elsewhere in the article, Begley defines “non-reproduced” as a term he assigned “on the basis of findings not being sufficiently robust to drive a drug-development programme.” This attitude is, of course, understandable in someone running an oncology drug development program for a major pharmaceutical company. He is looking for results that he can turn into FDA-approved drugs that he can bring to market before his competitors do. So what he does is more than just try to reproduce the results as described in the publication. His team of 100 scientists tries to reproduce the results and extend them to multiple model systems relevant to drug design. That is, in essence, applied science. Think of it this way: How many basic science discoveries in physics and chemistry ever get turned into a product? How many of these findings are sufficiently robust and reproducible in multiple model systems to justify a team of engineers to spend millions of dollars developing them into products? Do physicists, materials scientists, chemists, and engineers obsess over how few findings in basic science in their fields can successfully be used to make a product?

I know, I know, apples and oranges. In medicine, those of us doing research do it in order to develop an understanding of a disease process sufficient to develop an efficacious new treatment. It’s a very explicit in what we do. However, sometimes we forget just how important it is to have a large, robust pipeline of preclinical results upon which to base translational research programs. Is the reason for the apparently declining percentage of basic science studies that are successfully translated into drugs more a function of the increasing ability of scientists, through large scale genomic and small molecule screens, to identify more and more potential molecular targets and potential drugs to use against them than of scientists doing something wrong? I also have to wonder if what Begley and Ellis are observing is the decline effect accelerated by 100 scientists prowling the scientific literature looking for experimental results they can turn into drugs. As I pointed out before, the decline effect doesn’t mean science doesn’t work, and, as I will point out here, Begley’s very methods would almost be expected to accelerate the decline effect.

The rest of the story

Don’t get me wrong. Although I find the premise of Begley and Ellis’ article to be misguided, there is important and disturbing information there. Unfortunately, the really important and disturbing information is not in Begley and Ellis’ paper. The omission of these critical pieces of information strikes me as a curious decision on the part of the authors and Nature editors.

For example, in the paper, we learn this:

In studies for which findings could be reproduced, authors had paid close attention to controls, reagents, investigator bias and describing the complete data set. For results that could not be reproduced, however, data were not routinely analysed by investigators blinded to the experimental versus control groups. Investigators frequently presented the results of one experiment, such as a single Western-blot analysis. They sometimes said they presented specific experiments that supported their underlying hypothesis, but that were not reflective of the entire data set. There are no guidelines that require all data sets to be reported in a paper; often, original data are removed during the peer review and publication process.

This is one reason that when I review papers I always ask if assays were performed in a blinded fashion, particularly when the results involve selecting parts of histological slides for any sort of quantification.

In an interview, however, we learn a lot more critical information:

When the Amgen replication team of about 100 scientists could not confirm reported results, they contacted the authors. Those who cooperated discussed what might account for the inability of Amgen to confirm the results. Some let Amgen borrow antibodies and other materials used in the original study or even repeat experiments under the original authors’ direction.

Some authors required the Amgen scientists sign a confidentiality agreement barring them from disclosing data at odds with the original findings. “The world will never know” which 47 studies — many of them highly cited — are apparently wrong, Begley said.

I find it very interesting that Begley didn’t mention this rather important tidbit of information in the Nature paper and why he and Ellis didn’t see fit to name names of studies for which non-disclosure agreements weren’t signed. One wonders if he (and the Nature editors) were concerned about litigation. In any case, the non-disclosure agreements obviously must predate the Nature paper. This tells me that Begley was in essence complicit in not revealing that his team couldn’t reproduce results, apparently not thinking such agreements to be too high a price at the time for access to reagents and help in the cause of advancing his company’s efforts. He’s willing to admit this in news interviews, apparently, but not in the Nature paper being used as a broadside against current preclinical drug development efforts.

Here’s another highly irritating passage from Begley and Ellis’ paper:

Some non-reproducible preclinical papers had spawned an entire field, with hundreds of secondary publications that expanded on elements of the original observation, but did not actually seek to confirm or falsify its fundamental basis. More troubling, some of the research has triggered a series of clinical studies — suggesting that many patients had subjected themselves to a trial of a regimen or agent that probably wouldn’t work.

Why do I say this is an “irritating” passage? Simple. It would have been very helpful if Begley and Ellis had actually named a couple of these “entire fields,” don’t you think? I suppose they probably couldn’t do that without indirectly revealing which papers whose results Begley’s team couldn’t reproduce. The lack of this information makes this jeremiad against how preclinical research is done today far less useful for actually fixing the problem than it might have been. Assessing the irony of a paper railing against current preclinical research methods that does not itself reveal its methods in sufficient detail to be evaluated or even its results except in fairly vague ways is again left as an exercise for SBM readers.

There are also many explanations for the variability in published research, as has been pointed out by other commentators. For instance, Nobel Laureate Phil Sharp homes in on one problem:

The most common response by the challenged scientists was: “you didn’t do it right.” Indeed, cancer biology is fiendishly complex, noted Phil Sharp, a cancer biologist and Nobel laureate at the Massachusetts Institute of Technology.

Even in the most rigorous studies, the results might be reproducible only in very specific conditions, Sharp explained: “A cancer cell might respond one way in one set of conditions and another way in different conditions. I think a lot of the variability can come from that.”

It’s true, too. I remember back in the late 1990s, several labs were having difficulty reproducing Judah Folkman’s landmark work on angiogenesis inhibitors, including the lab where I was working at the time. Dr. Folkman provided reagents, protocols, and advice to any who asked, and ultimately we were able to find out what the problem was, part of which was that the peptide we were using was easily denatured. We also learned that he had done the same thing for several labs, even to the point of dispatching one of his postdocs to help other investigators. Now imagine if Folkman had been like one of the scientists who had demanded non-disclosure agreements when Begley’s group had trouble reproducing his studies.

Still, the problems with Begley and Ellis’ article notwithstanding, they do provide useful information and identify what appears to be a serious problem. The problem is not so much that so few basic science discoveries end up as drugs, courtesy of Amgen or one of its big pharma competitors. Rather, it’s the sloppiness that is too common in the scientific literature, coupled with publication bias, investigator biases, and the proliferation of screening experiments done to identify genomic targets and small molecules with biological effects that has turned into the proverbial fire hose of data, often many terrabytes per screen. I also wonder if part of the problem is that all the “easy” molecular targets for therapy have already been identified, leaving the difficult and problematic ones. The result is alluded to but not adequately discussed in the news story I cited above:

As recently as the late 1990s, most potential cancer-drug targets were backed by 100 to 200 publications. Now each may have fewer than half a dozen.

The genomics, proteomics, and metabolomics revolutions that have occurred over the last 10-15 years are largely to blame for this. I would also argue (and perhaps Begley would even agree) that the competitiveness between pharmaceutical companies to be the “firstest with the mostest” for each new target hyped in the medical literature almost certainly contributes to this problem. After having been burned a few times, Begley could, for instance, have decided that his team wouldn’t seize on each of these new papers, that he’d wait until some more papers were published. He didn’t do that. For him, business as usual continued. An admission that he was part of the problem, either in the Nature paper or one of the interviews he gave to the press, would have been nice.

How to improve preclinical research

It’s true that I’ve been critical of Begley and Ellis’ article, but that’s mainly because of frustration. There are many things that need to be improved in terms of how science is applied. Readers might recall that I’ve written about problems with the peer review system, publication bias, the decline effect, and numerous other problems that interfere with the advancement of science and contribute to doubts about its reliability. Such problems are inevitable because science is done by humans, with all their biases, cognitive quirks, and conflicts of interests, but that doesn’t mean every effort shouldn’t be made to minimize them. Science remains the single best system for determining how nature works, and, no matter how much quacks and cranks might try to cast doubt on it because it doesn’t support their pseudoscience, no one has as yet developed a better system.

The question, therefore, is how to minimize the effects these problems have on how the scientific method is practiced, particularly given that the scientific method itself is designed to try to minimize the effects of human shortcomings on how evidence is gathered and analyzed. No matter how much cranks like Vox Day and Mike Adams’ minions try to portray Begley and Ellis’ article as an indictment of science itself, as slam dunk evidence that that science is not self-correcting and the scientific basis of cancer therapy is so much in doubt that quackery is a viable alternative or that religion is a more reliable way of seeking knowledge about the world than science, it is in fact nothing of the sort.

It does, however, tell us that we as scientists need to improve, and, indeed, we at SBM have discussed the shortcomings of medical science and ways to improve upon it on many occasions. In fact, I daresay that much of what we say jibes with the suggestions proposed by Begley and Ellis, including:

• More opportunities to present negative data.
• An agreement that negative data can be as informative as positive data.
• Requiring preclinical investigators to present all findings.
• Links added to articles to other studies that show different or alternate results.
• Transparent opportunities for trainees, technicians and colleagues to discuss and report troubling or unethical behaviours without fearing adverse consequences.
• “Greater dialogue should be encouraged between physicians, scientists, patient advocates and patients. Scientists benefit from learning about clinical reality. Physicians need better knowledge of the challenges and limitations of preclinical studies. Both groups benefit from improved understanding of patients’ concerns.”
• More credit for teaching and mentoring.
• Less emphasis on publication in top-tier journals.
• “Funding organizations must recognize and embrace the need for new cancer research tools and assist in their development, and in providing greater community access to those tools. Examples include support for establishing large cancer cell-line collections with easy investigator access (a simple, universal material-transfer agreement); capabilities for genetic characterization of newly derived tumour cell lines and xenografts; identification of patient selection biomarkers; and generation of more robust, predictive tumour models.”

Many of these are good ideas, although I’m not sure how practical it would be to require that investigators present “all” findings in journal articles and how such a requirement would be enforced. Defining “all” would be a challenge, and online supplements are already too much of a dumping ground these days. For example, does “all” mean investigators have to present the dozens of attempts it might have required to optimize assay conditions or include every experiment that was screwed up because someone used the wrong conditions or added the wrong reagent or left their tubes sit on the bench too long? Also, one notes how Begley assiduously avoids criticizing pharma for being so eager to leap on the latest cutting edge research before it has percolated through the literature, which, I conclude based on his very own complaint, is surely part of the problem.

So is the very nature of science. Scientists know that what is published the first time is considered tentative. It may or may not be correct. We also know that publication bias can mean that the first publication of a result might well be an anomaly that was published because it was interesting. That is science at the frontier. If other scientists can replicate the results or, even better, replicate the results and use them as a foundation to build upon and make new discoveries, only then does such a result become less frontier science. And if the results are replicated enough times and by enough people and used as a basis for further discoveries, to the point that they are considered settled results, that’s when they become applied science, such as a drug based on the principle originally discovered. It’s a process that is very messy and with lots of dead ends and blind alleys that go nowhere. While performing a valuable service that identifies problems with a lack of reproducibility in all too many preclinical cancer research studies, Begley and Ellis also unfortunately contribute to the mistaken impression that translational research is a linear process that goes from discovery to drug. It’s not, nor can it churn out major new treatments on demand.

Raw Milk

In Oregon we are having a small outbreak of infections from consumption of raw milk.  Not a surprise, since milk is a wonderful culture media and the udder is just down the gravity well from the cows anus.  Raw milk violates the classic dictum “Don’t shit where you eat” although I understand the saying concerned dating in its original conception.

Although the sale of raw milk is illegal in muchof the US,  the law can be bypassed by owning the cow rather than buying the milk,  a reverse of dating advice.  Such is the case in Oregon, where 48 people are time sharing the cows responsible for the current outbreak.  There has been the spread of pathogenic E. coli to at least 5 people, mostly  children, and has lead to the hospitalization of at least 3 children.

Of course, it is hard to get infected. Humans have lived in Filth and Squalor (like Minneapolis and St. Paul or Buda and Pest) for centuries, drinking and eating contaminated food and enough survived perpetuate the species.  Most infections in the past would have been from consuming contaminated food and drink.  I have wondered if the reason fevers are often associated with diarrhea and/or vomiting is that it an evolved response for removing infected material as soon as possible.

The CDC has reported multiple  outbreaks of infection traced to consuming raw milk, not that anyone is paying any attention.  The results were recently summarized:

The study included 121 dairy–related disease outbreaks, which caused 4,413 illnesses, 239 hospitalizations and three deaths. In 60 percent of the outbreaks (73 outbreaks) state health officials determined raw milk products were the cause. Nearly all of the hospitalizations (200 of 239) were in those sickened in the raw milk outbreaks.  These dairy-related outbreaks occurred in 30 states, and 75 percent (55 outbreaks) of the raw milk outbreaks occurred in the 21 states where it was legal to sell raw milk products at the time. The study also reported that seven states changed their laws during the study period.

Consumers can’t tell if raw milk is safe to drink by looking at, smelling, or tasting it. Even under ideal conditions of cleanliness, collecting milk introduces some bacteria.  Unless the milk is pasteurized, these bacteria can multiply and grow in the milk and cause illness. Pasteurization involves heating milk to kill disease-causing bacteria.

It is rare to get infections from milk:  it is estimated that 1% of milk is consumed raw, about 27 billion pounds.  Lets see. A pint is a pound the world a round, so that’s 54,000,000,000 cups drunk drank drunken consumed for 4400 illnesses.  Not a huge risk, although children were disproportionately affected (60%) and E. coli 0157 mediated hemolytic uremic syndrome (HUS), with kidney failure and occasional deaths are reported.

Not that it makes any difference to those who believe in the unproven benefits of raw milk over safe food:

…people who drink raw milk tend to be fierce advocates. One person, who posted anonymously on Oregonlive.com, said that he or she would not stop drinking milk from Foundation Farm even though it had sickened the commentator and the commentator’s 2-year-old child.

The inability to admit error boggles the mind.

“ Two simple words. Two simple words in the English language: “I forgot!” How many times do we let ourselves get into terrible situations because we don’t say “I forgot”? Let’s say you’re on trial for giving your kid HUS from raw milk. You say to the judge, “I forgot raw milk is contaminated with dangerous bacteria.  Let’s suppose he says back to you, “You have committed a foul crime. You killed your child by deliberately giving them milk contaminated with cow manure, and you say, ‘I forgot’?” Two simple words: Excuuuuuse me!!”

Rhinos and Tigers and Bears. Oh my.

“I would personally kill every chimpanzee on the planet with my bare hands if it meant saving one homeless crack-addict with AIDS.”
~ Penn Jillette

I don’t know. I have met some pretty nice chimps and some remarkably evil crack-addicts. I suspect he would be more protective of our evolutionary cousins if the choice were between chimps and some of his colleagues on The Apprentice, but perhaps I read body language incorrectly. But I would not kill a single animal for any Traditional Chinese Medicine (TCM) nostrum.

Several years ago I summarized the adverse effects of Traditional Chinese Medicine on the environment and other species.  It is not uncommon to grind up endangered animals and plants such as rhino horn, tigers and antelope for medicinal purposes.  Their efficacy is less than plausible; rhino horn is basically hair and will not even cure baldness.  But use of TCM is increasing, consuming plants and animals with a Galactus-ian  hunger.  There is big money to made in puree of endangered species.

The issue with many of the supplements from India, China, and the US  is quality control.  What is on the label may or may not be what is in the tablet.  But how can you tell if your TCM nostrum is filled with toxins or a melange of mammals?  Modern technology has the answer. Or magic.

Targeting both the p-loop region of the plastid trnL gene and the mitochondrial 16S ribosomal RNA gene, over 49,000 amplicon sequence reads were generated from 15 TCM samples presented in the form of powders, tablets, capsules, bile flakes, and herbal teas. Here we show that second-generation, high-throughput sequencing (HTS) of DNA represents an effective means to genetically audit organic ingredients within complex TCMs. Comparison of DNA sequence data to reference databases revealed the presence of 68 different plant families and included genera, such as Ephedra and Asarum, that are potentially toxic. Similarly, animal families were identified that include genera that are classified as vulnerable, endangered, or critically endangered, including Asiatic black bear (Ursus thibetanus) and Saiga antelope (Saiga tatarica). Bovidae, Cervidae, and Bufonidae DNA were also detected in many of the TCM samples and were rarely declared on the product packaging.

They also found toad, goat, sheep, buffalo, and cow DNA in some of the concoctions.  Listed ingredients, when they bothered to list them, included toad cake,  testis et penis callorhini, and cow and monkey bezoar. Almost makes raw milk appear palatable by comparison.

Consumers of TCMs need to be wary of honesty of food labelling , as in 78% of samples, animal DNA was identified that had not been clearly labelled on the packaging (in either English or Chinese). This adulteration of medicine occurred in the Saiga Antelope Horn powder  which claimed to be 100% pure, yet was found to also contain significant quantities of goat (Caprine) and sheep (Ovine) DNA. In some TCMs, undeclared ingredients are used to reduce the cost of manufacture of the medicine by increasing the bulk of the powder, but it is impossible to determine why Caprine and Ovine appeared in this product. Water buffalo (Bubalus bubalis), domestic cow (Bos taurus) and deer species were also not listed on the packaging of samples in which they were genetically identified. The inadvertent consumption of undeclared animal products found in 78% of the medicines, such as bovid, risk violating certain religious and/or cultural strictures.

What?  I am using adulterated quackery instead of pure quackery?  Consumers of TCM have more to worry about than honesty in food labeling, as if somehow lying about nonsense is worse than honest nonsense.

The take home is when you use TCM products, you are likely contributing to the extinction of species even when the label on the  nostrum appears safe. You are not even saving a homeless crack-addicted AIDS patient, much less helping yourself.

Like Cure Like

Not.

It has been a while since I pursued the Pubmeds on homeopathy.  Regular readers of the blog know the fantasy based premises of homeopathy.  Substances that cause symptoms, when diluted beyond any residual presence, will cure the disease.

Most of the time trying to test this fantasy  is messy.  There are a lot of diseases, but fewer symptoms.  There are a lot of potential  variations in fevers or headaches or sinusitis that result in choosing a homeopathic remedy being “individualized.”  Despite being fantasy based, the enormous variation makes it hard to test one homeopathic cure for one illness or symptom.  The wiggle room is enormous.

Testing ‘like curing like’ would be more straightforward if it were poisoning.  Lead or arsenic poisoning would seem a straightforward condition to test homeopathic validity.  You would know exactly which like would cure which like. Lead toxicity should be cured with homeopathic lead.   And, incredibly, such studies have been done.

And, at least for lead, like does not cure like:

INTRODUCTION:
Poisoning due to lead and its compounds has short and long-term effects primarily on the nervous, hematopoietic, gastrointestinal, cardiovascular, musculoskeletal, renal and reproductive systems. It can manifest in acute or chronic symptoms. Measuring serum concentration is the primary method for diagnosing and monitoring exposed workers. Presently, elevated lead levels are treated by drugs whose effectiveness is contested on various fronts. Experimental studies suggest that homeopathic preparations may be in controlling blood lead levels in laboratory animals, creating the need for controlled studies to evaluate the effectiveness and safety of these preparations in humans.
OBJECTIVE:
To evaluate the effectiveness of the homeopathic preparation Plumbum metallicum in reducing the blood lead level of workers exposed to this metal.
DESIGN:
Double-blind randomized trial.
SETTING:
Workers’ clinic in the Ajax battery plant, which employs 900 workers with varying degrees of lead exposure in Bauru, São Paulo State, Brazil.
SUBJECTS:
131 workers exposed to lead.
INTERVENTION:
Plumbum metallicum 15 cH or placebo, orally for 35 days.
RESULTS:
The percentage of workers who demonstrated a reduction in lead counts by a percentage greater than or equal to 25% following treatment was the same for both groups: 20.3% in the homeopathic groups versus 21% in the control group [Relative Risk (RR) = 0.95, confidential interval (CI) 95%: 0.47-1.92)]. Analysis by intention-to-treat also did not show any difference between the groups: 18.2% in the treated group versus 20% in the placebo group (RR = 0.91, CI 95%: 0.45-1.84).
CONCLUSION:
The homeopathic preparation Plumbum metallicum had no effect, in this study, in terms of reducing serum lead in workers exposed to lead.”

What a surprise, although one wonders what they were thinking in the Institutional Review Board at the  Federal University of São Carlos for allowing such a study to be done.

A similar study, this time with arsenic, was done in China.  And you have to love the description of how ‘informed’ consent was obtained

Most arsenic victims were weak and anemic and therefore concerned about giving blood at regular intervals. They were in general frustrated and almost resigned to their fate. They signed informed consent on the basis of the agreement that they would provide samples of their urine and blood only twice; once on the day before they started taking the “verum” or “placebo”, and then 2 months after administration of the “verum” or “placebo”.

Half of the 28 subjects dropped out,  resulting in nine people in the treatment group and 5 in the placebo.Any conclusion would be 200C. The researchers seem to be unaware that multiple measurements in small numbers of subjects with multiple statistical analysis will find something ‘significant’ but are  are as meaningless as the underlying premise of the study.

From the results of this pilot study, it becomes obvious that the verum-fed group showed positive ameliorating effects, like that of the other potencies of centesimal dilutions, Ars Alb 30C and Ars Alb 200C reported earlier. Since Ars Alb LM 0/3 potency can be used for a long time and since this remedy also has protective abilities in subjects living in a village where arsenic-free drinking water facility was unavailable, this could be used as an interim measure, particularly in remote villages without having any other kind of medical facility. As a higher potency may actually be required for sustaining the ameliorative effects, it is recommended that the remedy be used under supervision of a practicing homeopath, who may suggest when the next higher potency ought to be used. Furthermore, change in symptoms may call for some intermittent remedy (may be a constitutional remedy) as based on severity of condition and totality of symptoms…
How the tiny globules soaked in the ultrahighly diluted remedy could bring about changes in so many parameters of study while the same could not be achieved by the Ars Alb LM 0/3 unsoaked globules (placebo) remain largely unknown. However, one working hypothesis advocated by Khuda-Bukhsh et al［17-19］ is that potentized homeopathic remedies may act as a “molecular switch” to trigger specific genes that may in turn activate/deactivate a cascade of other relevant genes may be one way of explaining such inexplicable phenomenon at the state of our present understanding.”

One would think in a town with arsenic in the water, that taking homeopathic water in large quantities would be of benefit, although they were limited to 10 drops twice a day. It is a town that actually needs a massive continual overdose of homeopathy:  potable water.  Finally a real use for homeopathy.  Oddly they used an Indian homeopathic preparation and given the propensity of other Indian SCAM products to be adulterated with arsenic, I would be fatalistic as well if asked to be in the study.

CAM is placebo. Placebo  is nothing.  Therefore CAM is nothing.

Several studies out this year emphasized the concept that it is the therapeutic interaction and the patients belief that is important for the subjective (but not objective, for there are none) responses to SCAM’s,  not the specific SCAM modality.  Two nonsensical SCAM interventions had the same result.

First was homeopathy  where

Homeopathic consultations but not homeopathic remedies are associated with clinically relevant benefits for patients with active but relatively stable RA.

The other was acupuncture. It has been know that acupuncture efficacy depends in part on how strongly the patient believes it will work.  This was confirmed in a study in Pain  where patients with osteoarthritis were treated with  acupuncture, Streitberger placebo acupuncture, and mock electrical stimulation, each with empathic or nonempathic consultations. The results supported the understanding that the only thing that matters for reported outcomes with acupuncture is the patients belief in its efficacy, although one practitioner had better results than the others:

Empathic consultations did not affect pain (3.0mm, -2.2 to 8.2; P=.26) but practitioner 3 achieved greater analgesia than practitioner 2 (10.9, 3.9 to 18.0; P=.002)… The 2 placebos were equally as effective and credible as acupuncture. Needle and nonneedle placebos are equivalent. An unknown characteristic of the treating practitioner predicts outcome, as does the patient’s belief (independently).

Why do I envision a Rasputin like  practitioner getting better results?  SCAM’s, like placebo effects, are self deception by the patient and practitioner.  N-Rays all the way down.

And if it were ethical, and it is not ethical since acupuncture is nonsense, you would be able to help the undiagnosed and perhaps undiagnoseable patient with a round of supportive acupuncture:

BACKGROUND:
Medically unexplained physical symptoms (MUPS) are common and difficult to treat.
AIM:
To investigate the effectiveness of adding five-element acupuncture to usual care in ‘frequent attenders’ with MUPS.
DESIGN AND SETTING:
Randomised controlled trial in four London general practices.
METHOD:
Participants were 80 adults with MUPS, consulting GPs ≥8 times/year. The intervention was individualised five-element acupuncture, ≥12 sessions, immediately (acupuncture group) and after 26 weeks (control group). The primary outcome was 26-week Measure Yourself Medical Outcome Profile (MYMOP); secondary outcomes were wellbeing (W-BQ12), EQ-5D, and GP consultation rate. Intention-to-treat analysis was used, adjusting for baseline outcomes.
RESULTS:
Participants (80% female, mean age 50 years, mixed ethnicity) had high health-resource use. Problems were 59% musculoskeletal; 65% >1 year duration. The 26-week questionnaire response rate was 89%. Compared to baseline, the mean 26-week MYMOP improved by 1.0 (95% confidence interval [CI] = 0.4 to 1.5) in the acupuncture group and 0.6 (95% CI = 0.3 to 0.9) in the control group (adjusted mean difference: acupuncture versus control -0.6 [95% CI = -1.1 to 0] P = 0.05). Other between-group adjusted mean differences were: W-BQ12 4.4 (95% CI = 1.6 to 7.2) P = 0.002; EQ-5D index 0.03 (95% CI = -0.11 to 0.16) P = 0.70; consultation rate ratio 0.90 (95% CI = 0.70 to 1.15) P = 0.4; and number of medications 0.56 (95% CI = 0.47 to 1.6) P = 0.28. All differences favoured the acupuncture group. Imputation for missing values reduced the MYMOP adjusted mean difference to -0.4 (95% CI = -0.9 to 0.1) P = 0.12. Improvements in MYMOP and W-BQ12 were maintained at 52 weeks.
CONCLUSION:
The addition of 12 sessions of five-element acupuncture to usual care resulted in improved health status and wellbeing that was sustained for 12 months.”

Positive interactions with other humans is always of benefit can improve the quality of life.  As I have said before, grooming each other has salubrious effects on apes.  The benefits of SCAMs are the medical equivalent of nit picking, without the ick factor of eating the louse.

And finally, are there Florence and the Machine fans who can tell me what this study is all about?  Clinical comparative study on the influence of acupoint sticking therapy in dog days and in non-dog days to the quality of life of allergic rhinitis patients.  I thought the dog days were so over.