e4-02: Herbal & Dietary Supplements

Across the world, there is a high prevalence of use of HDS. According to the World Health Organization, the use of HDS in the United States has increased significantly over the past two decades. Depending on the survey, more than 50% of respondents report using an HDS in the past 30 days. While used by all populations and all socioeconomic backgrounds, studies consistently show that women use HDS more than men, and family households with greater wealth also use more. Finally, older adults tend to be the highest consumers of HDS, with nearly 70% taking an HDS in the past 30 days.

As of 2018, 124 Member States (64%) responded that they had laws or regulations on HDS. Specific to the United States, in 1994, the US Congress passed the Dietary Supplement and Health Education Act (DSHEA). This legislative act defined a dietary supplement as a product (other than tobacco) that is intended to supplement the diet; contain one or more dietary ingredients (including vitamins; minerals; herbs or other botanicals; amino acids; and other substances) or their constituents; is intended to be taken by mouth as a pill, capsule, tablet, or liquid; and is labeled on the front panel as being a dietary supplement. Under this law, supplements can be marketed without proof of safety or efficacy if no claim is made for their use in the diagnosis, treatment, cure, or prevention of disease. Manufacturers can, however, make “structure and function” claims that a product enhances a normal body function or state. For example, saw palmetto can be marketed to support urinary tract health but not to treat benign prostatic hyperplasia. In contrast to prescription medications, which must be proven safe, the US Food and Drug Administration (FDA) must first prove that an HDS is unsafe before a product is taken off the market. In 2006, the US Congress passed the Dietary Supplement and Nonprescription Drug Consumer Protection Act, which updated DSHEA so that dietary supplement producers were responsible for reporting serious adverse events related to their products. In addition, in 2007, the FDA published current good manufacturing practice guidelines, including requirements for manufacturers to test products to ensure product quality, confirm the absence of some contaminants, verify accuracy of labeling, maintain minimum standards for manufacturing and packing, monitor adverse event reports, and make all records available for FDA inspection. However, these guidelines are nonbinding on the manufacturer. Since 2007, the FDA has increased inspections of HDS manufacturers and enforcement of regulations. Other countries, including Canada, Australia, and Japan, as well as the European Union, have stricter policies on the licensure and marketing of HDS. Patients should be advised to follow certain guidelines when using HDS (Table e4–1). In 2019, the FDA reported that they will be updating the regulation of HDS to continue to promote safety, quality, and efficacy. They began to use a different electronic submission system for notification of new dietary ingredients as well as structure/function claims.

One challenge in the commercialization of HDS pertains to product formulation and standardization. To ensure a consistent percentage of the primary active ingredients across batches and brand names, standardized extracts have been developed for certain HDS. One example is the German Commission E. This scientific advisory board has played a significant role in standardized HDS, especially requiring that formulations contain consistent quantities of marker compounds (which may or may not be the principal active ingredients). This work has also laid the foundation for conducting phase 2 and phase 3 clinical trials.

While many HDS are safe, a few have significant toxicity. One well-known example is ephedra, an extract of the plant Ephedra sinica (known in Chinese medicine as “ma huang”). This HDS has been banned in the United States due to case reports of severe and fatal reactions, including sudden cardiac death, myocardial infarction, and stroke. Ephedra contains alpha- and beta-receptor agonists that can lead to profound sympathetic nervous system stimulation and consequent increased blood pressure, vasoconstriction, increased myocardial stress, and dysrhythmia. Case reports of ephedra's toxicity occurred when the HDS was used in very high doses, often in combination with caffeine, as an over-the-counter weight loss supplement.

Other cases of HDS toxicity have occurred when the plant is used inappropriately, either in excess as an extract or out of the medicinal context in which it was historically developed. HDS products have also been adulterated with prescription medications or contaminated with harmful substances such as pesticides or heavy metals. For example, prescription medications such as prednisone, nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, and testosterone have been detected in imported Chinese HDS.

Twenty-five percent of patients who take prescription medications also take at least one HDS, creating a theoretical risk for HDS-HDS or prescription drug–HDS interactions. This figure increases to 50% in older US adults who take prescription medications. Although many interactions are not clinically significant, the risk of interaction must be assessed. Resources for busy clinicians to check for interactions between prescription products and HDS are Natural Medicines (trchealthcare.com/natural-medicines/) and MicroMedex (www.micromedexsolutions.com). A resource for independent third-party testing of purity and safety of commercial products is ConsumerLab.com (www.consumerlab.com). In the case of suspected adverse interactions, clinicians should take a detailed history from the patient and, if possible, obtain a sample of the product to facilitate further analysis, if needed. All suspected adverse events should be reported to the FDA's MedWatch Program (https://www.fda.gov/safety/medwatch-fda-safety-information-and-adverse-event-reporting-program). Across the world, according to the WHO, less than half of member countries have post-marketing surveillance systems in place for safety and adverse events.