How Physicians Should Evaluate Dietary Supplements

I found this older article in a pile of stuff "to blog" about and gave it a quick look over. It seems like a nice refresher for those who are unaware of some of the history about hos the US got to where we are presently when it comes to the regulation of dietary supplements. The authors describe a number of limitations to this regulation strategy which leave supplements inherently flawed. For example, products are not tested and held to standards regarding active ingredients, but are instead usually "standardized" based on the amount of ingredients that are put into the mixer. As such you may have varying amounts of ingredients depending on (just to name a few):

• cultivars vs. wild growth
• misidentification of plants
• stage of growth at harvest
• environmental conditions during growth
• methods of harvest and processing
• misidentification of plant parts (leaf vs. berry)
• environmental contaminants (heavy metals, microbes, insects)
• improper storage
• variations in temperature, moisture, or light
• effects of solvents on active ingredients
• binders and fillers in capsules affecting bioavailability

To answer the "What's the harm?" question, the authors briefly discuss ephedra and its aggressive marketing and misuse in the 90's which led to several reported deaths and who knows how many unreported injuries, hospitalizations, and fatalities. I was surprised, then, when the authors took a very soft conclusion on how they suggest clinicians address these issues with patients. They suggest that taking a history which includes supplement use is important, which I agree with. The authors do not, however, encourage the cessation of supplements, not even for those without evidence. Perhaps I misread the conclusions, but I would have thought that it would be generally good advice to avoid taking unproven remedies with no guarantees of safety and the potential for adulteration with unknown contaminants.

Curious, I looked further into the credentials of the senior author, Larry A. Walker PhD. He is on faculty at Ole Miss. He also serves as a member of the National Advisory Council for the NCCAM. His PubMed results are a little hard to weed through since "walker LA" is a relatively common name and many results go to research which appears outside his scope. His google search results were interesting. Of the first couple of dozen, many point to identical text in which Dr. Walker seems to be supportive of a mushroom-based product for immune support, and specifically a compound called "grifolan". So this is where I decided to indulge in a little trip down Alice's rabbit hole of the internet.

The text is quoting him could easily be taking some other reference out of context and I have no idea if he actually supports the product making the claims. So, I added "grifolan" to PubMed for "walker LA", but that does not yield any results. Searching for "grifolan" alone does generate 44 results, with several reviews of its benefits and, perhaps not surprisingly, no actual experiments involving actual humans. What is really amusing is to search google for "grifolan larry walker" which gets you dozens and dozens of websites all selling mushroom extracts and using the exact same quote: 

"Grifolan has been shown to activate macrophages, a type of cell consider the " heavy artillery": of the immune system, explains Larry A. Walker, Ph.D"

This amazing stuff seems to be good for diabetes, hepatitis, and is even sold at naturalpetrx.com. The echo chamber continues on as I found an Amazon reviewer who has three reviews of different herbal products, each of which reads like it is copied right of the back label of the bottle. Fascinating how out of the ether, internet traffic and content that is posted and reposted can eventually build into something appearing to be based in fact, despite a mere handful of actual scientific studies.

The "pharmaceutical inverse benefit law"

You may be aware that there are several forces of nature that behave in an inverse square relationship. For example, if you move a certain distance away from an object, the gravity between you and that object decreases by the square of the difference. This also holds true for light, sound, radiation, and other forces.

Based on that principle, two researchers named Brody and Light have suggested that the benefit/harm ratio of a given drug in inversely proportional to the amount of pharmaceutical marketing applied. For example, sleeping pills which are not much more effective than an over-the-counter antihistamine, are marketed with forces often reserved for beer and pizza.

In their article suggesting this hypothesis, they go on to detail several marketing strategies which might be utilized at gaining market share, increasing prescription drug use, and changing how people prescribe.

Reducing diagnostic thresholds - Cutoffs to diagnose diabetes have drifted down over the years, but little evidence suggests that aggressively reducing blood sugar improves outcomes. But lower cutoffs might prompt people to prescribe more drugs anyway. My response: definitions of diseases change over the years, sometimes for the better. Homosexuality used to be considered a psychiatric disease.

Surrogate end points - Some studies do not measure death or heart attacks as outcomes, but instead measure cholesterol levels or blood pressure. This makes it easier to get drugs to market (since the studies can me much smaller). Some drugs, which show promise with these outcomes, go on to show no benefit with later studies of important outcomes (see torcetrapib). My response: Sometimes surrogate end points are the only ones suitable for study because finding 10,000 patients to follow over 5 years is tough and expensive.

Exaggerated safety and efficacy claims - This is easy to imagine. Upsell the good stuff and downplay the bad.

Creating new "diseases" - Prehypertension and prediabetes potentially expands the number of people to be treated. If this reduces bad outcomes, this could be good for patients, but even if it does not, more people on medications is good for the bottom line of pharmaceutical companies.

Encouraging unapproved uses - Drug company reps are not allowed to talk about uses for drugs that are not approved by the FDA. They can, however, hire doctors to talk about "off-label" uses. My response: this is true and certainly invites the possibility for bias, but many drugs are used off-label to good effect.

So, is there an inverse benefit law? It is not easy to measure but if someone is looking for a research project you probably could count drug ads and compare that to the relative risk reduction of drugs to measure the relationship, I certainly would not be surprised if someone proved it.