The anti-supplement letter-writing campaign from Sen. Claire McCaskill (D-Missouri) shows no sign of letting up. Her office announced the senator has sent letters to several key medical associations in an effort to learn more about how physicians advise patients on the risks of potential interactions when using dietary supplements concurrently with common drug therapies.

Make no mistake. McCaskill, ranking member of the Special Committee on Aging, is talking potential herb-drug interactions and risks, but her sights are on the regulation of the overall dietary supplement industry.

“The fact is that we don’t know enough about how dietary supplements interact with cancer treatments—or with the treatment of other serious conditions," McCaskill said. “The lack of consumer protection in the dietary supplement industry has left patients facing life-threatening illnesses even more vulnerable. I can’t sit by while their health and safety is compromised just because our regulatory scheme for dietary supplements is flawed."

The letter recipients included the American Medical Association, the American College of Physicians, the American Society of Clinical Oncology, the American Geriatrics Society, the American Cancer Society, the National Medical Association, the American Osteopathic Association, the Gerontological Society of America, the National Hispanic Medical Association, and the American Pharmacists Association.

In an excerpt of a letter included in her press release, McCaskill cited a recent Wall Street Journal article on how dietary supplements interact with drugs as well as herb-drug interaction research from the University of Minnesota highlighted in the article:

She claimed the issue with herb-drug interactions is particularly troubling because research has shown as many as 70 percent of patients do not tell their doctors about alternative therapies they are taking, and this communication lapse raises the risks associated with any interactions, especially during cancer treatment.

“Given these concerns, I am reaching out to prominent professional associations and other leaders in the medical field concerning the guidance they provide, if any, to physicians on the interactions between dietary supplements and cancer treatments," she wrote. “Ensuring the health and safety of our seniors is one of the most important aspects of my role as Ranking Member on the Special Committee on Aging, and I greatly appreciate your assistance with this matter."

Drew Pusateri, communications director for McCaskill in the Aging Committee, said while such letters usually include a deadline for response, there was no such deadline given to the associations receiving the letters. However, he noted, “We expect them to respond."

Dan Fabricant, Ph.D., executive director and CEO of the Natural Products Association (NPA) and a former dietary supplement regulator at FDA, had a sharp counter for McCaskill’s view. “There’s not a product or supplement on the planet that is designed to interact with cancer patients undergoing chemotherapy," he stated. “Plenty of foods such as grapefruit juice can cause potential interactions in patients taking prescription drugs, and that’s why it’s important for anyone thinking about taking a supplement to speak first with a doctor."

As far as McCaskill’s using herb-drug interactions to further her attempts to change supplement regulation, Fabricant was blunt. “Does Senator McCaskill really want the FDA to do what doctors took an oath to do?" he asked. “It’s absurd to suggest that the FDA should get between a doctor and a patient."

The American Herbal Products Association (AHPA) has a long-standing policy to recommend that consumers of herbal supplements inform their healthcare provider(s) of such use, advised Michael McGuffin, AHPA’s president. “In the interest of seeing this recommendation broadly accepted by consumers, AHPA encourages healthcare providers to receive such communication with respect for the consumers’ healthcare choices and also encourages healthcare providers to seek out accurate and truthful information about herbs," he added.

Fabricant added NPA has also gone above and beyond what is required by federal law to offer third-party certification for its member companies and other supplement manufacturers. “We are committed to educating consumers and the public about the safe use of dietary supplements and natural products and strongly encourage the FDA to use all of the resources at its disposal to do the same," he said.

Industry also took issue with McCaskill’s reliance on the study from Rui Zhang, Ph.D., and his colleagues from the University of Minnesota.

“The suggestions in the Zhang article that so many herbs have significant interactions with so many drugs is not consistent with other published scientific articles on this subject which have concluded, for example, that echinacea, kava, and ginseng supplements are unlikely to have clinically significant effects on conventional medicines," McGuffin said. “Nor does the Zhang article present any new research."

The research used “semantic prediction" to perform a computer search of Medline indexed studies to look for keywords that might indicate an herb-drug interaction. They used a unique machine learning-based filter to rank the prediction results by probability of being correct. They extracted more than 10,000 predictions involving herbs and various genes and drugs, and found 69 percent of the top-ranked predictions was around 69 percent. “However, due to its limited recall and precision, human review is typically required for maximally effective use of this resource," the researchers wrote. They noted a drug interaction expert who is both a pharmacist and physician manually reviewed the top 100 ranked interactions found.

The researchers reported finding known interactions, but they also discovered unknown interactions, which was the primary goal. In fact, they noted while many specific interactions between Echinacea and cancer drugs are well-known, they uncovered new interactions in this area.

“Having been in the clinical herb-drug interaction arena for almost 20 years, I can assure you that this ‘new’ approach is certainly not the definitive means of assessing whether or not a particular botanical is prone to interact with conventional medications," said Bill Gurley, Ph.D., professor of pharmaceutical sciences at University of Arkansas for Medical Sciences. “I have conducted several clinical herb-drug interaction studies with Echinacea, kava and ginseng and, in my opinion, their risk for interaction is low.  What people fail to realize is that not all botanical supplement formulations are created equally, and the interaction potential is dependent on a host of factors."

The University of Minnesota researchers admitted such limitations. “Verifying such interactions is a significant challenge for this type of methodological development since, by definition, there is no reference standard," they wrote. “The best validation method would be to translate the findings into a clinical trial for the suggested combination."

In his 2012 series in Planta Medica journal (Parts one and two), Gurley explained that humans process dietary chemicals and drugs—single chemical entities often derived from plants—in a similar way, which is why there are a number of possible drug-drug, drug-food (fruits, vegetables) and drug-herb interactions. While he noted herb-drug interactions can lead to reduced drug efficacy or even undesirable episodes, many interactions found in vitro rarely show up in vivo.  

“Despite exposure to thousands of structurally diverse dietary phytochemicals, only a few appear to significantly modulate human drug metabolizing enzymes and transporters," Gurley wrote.

As part of his Planta Medica herb-drug interaction series, Gurley and his colleagues examined the scientific literature to assess the risk of herb-drug interactions when conventional medicines are taken concomitantly with popular dietary supplements Echinacea, ginseng and kava, as well as garlic, goldenseal, milk thistle and ginkgo biloba.

“Most botanical dietary supplements pose minimal risk of modulating human drug metabolism," they concluded, noting poor dissolution is an obstacle to bioavailability and efficacy. “Several dietary supplement manufacturers have recently incorporated novel methods of formulating botanical extracts as a means of improving oral absorption … many botanicals whose drug interaction potential is minimized when administered as conventional dry extracts may increase significantly upon ingestion of formulations utilizing novel delivery systems."

Stefan Gafner, chief scientific officer for the American Botanical Council (ABC), noted the topic of herb-drug interactions has risen in prominence over the past few years, as academic and industry researchers have been more active in this area of study. “It is also one of the priorities of the NCCIH [National Center for Complementary and Integrative Health], which has initiated a call for applications to a new Center of Excellence for Natural Product - Drug interaction research," he added.

In addition, Gafner noted industry and academic researchers have started an initiative to harmonize in vitro test protocols to evaluate possible herb-drug interactions, as published in HerbalGram 107, and HerbalEGram.

“I have heard from physicians and pharmacists alike that they do not know where to find data on herb-drug interactions," Gafner said, highlighting several databases and books that contain information on herb-drug interactions, such as the ABC Clinical Guide to Herbs, the AHPA Botanical Safety Handbook, 2nd edition,  Max Wichtl's book "Herbal Drugs and Phytopharmaceuticals" (the latest edition is only available in German) and the Natural Products Comprehensive Database, which Gafner called the most extensive database on herb-drug interactions. ABC also suggested the database by Francis Brinker (ND) based on his book Herb Contraindications & Drug Interactions (from Eclectic Medical Publications) is also an excellent evidence-based compilation, with online access to newer data since the publication of the latest version. 

Pusateri noted McCaskill did not reach out to botanical-related associations and other sources of herb-drug interaction references, as the primary focus was on the medical associations. “Right now our goal is to learn more about what doctors are hearing from the medical associations about herbs and potential interactions," he told INSIDER.

Figuring out what guidance doctors and healthcare providers receive in the area of herbs and potential interactions with common medicines is one thing, but highlighting the University of Minnesota study and calling out supplement regulation is a tactic the supplement industry opposes.

Gafner emphasized the points made about in vitro studies on isolated enzymes often turn out to lack clinical significance, but noted there are  some notable examples of relevant herb-drug interactions, e.g., St. John's wort is known to interact with a large number of drugs, including anticancer drugs.

“As such, the publication by the researchers from the University of Minnesota is providing data on possible interactions, but with the caveat that it is unclear if these interactions are actually relevant in the clinical practice, or if these are only happening in theory," Gafner said. “As an example, the study predicts that Echinacea spp. will interact with docetaxel (Table 1), while a small clinical trial (Goey et al, 2013, British Journal of Clinical Pharmacology) suggests that Echinacea can be safely used in combination with docetaxel."