Considering clinically relevant herb-drug interactions 30 years on
In a new paper published in the Journal of Dietary Supplements, Bill Gurley, PhD, principal scientist at the National Center for Natural Products Research at the University of Mississippi, looks back at three decades of dietary supplement usage in a market that has evolved from a few hundred products made up mostly of vitamins, minerals and select botanical extracts to more than 75,000 single- and multi-ingredient products. During this period, one of the fastest-growing segments has been products formulated with botanicals.
“Coincident with the growing popularity of botanical dietary supplements (BDS) has been their concomitant ingestion with conventional prescription medications,” Dr. Gurley noted. “BDS are complex mixtures of phytochemicals oftentimes exhibiting complex pharmacology.”
Formulated as concentrated phytochemical extracts, they contain a variety of plant secondary metabolites rarely encountered in the typical diet, he added, which when taken with prescription drugs could lead to clinically significant herb–drug interactions (HDI).
A long history of plant medicine
People and animals have benefited from the therapeutic properties of plants since the beginnings of time, with the use of botanical extracts establishing itself as phytomedicine across cultures over millennia.
In the New World, botanicals were a mainstay in American medicine from the earliest settlements when the first colonists of the 17th century used a variety of imported and endemic herbs and traditions to treat conditions ranging from dysentery to syphilis. Among the most popular plants, roots and other natural products were snakeroot, dittany, senna, alum, sweet gums and tobacco, according to historian Thomas P. Hugues, writing of the history of the medicine in the Jamestown settlement from 1607 to 1699.
The United States Pharmacopeia (USP), a compendium of standards and quality tests for plants and herbs sold in chemist or druggist shops, first published in 1820, and the United States Dispensatory (USD) served as a complimentary body of quality tests and specifications for confirming composition, purity, strength and uses from 1833 to 1973.
“For more than 140 years, American physicians and pharmacists relied upon scholarly monographs published within these two official compendia which detailed a litany of pharmaceutical preparations for treating various diseases and disease symptoms; the vast majority of these were plant based,” Dr. Gurley wrote. “Thus, botanical extracts with their multiplicity of plant secondary metabolites (PSM)—resident phytochemicals used in defense against herbivores, pathogens and other plant species—were a driving force in American medicine throughout the 19th century and the first half of the 20th century.”
The discovery of antimicrobial sulfonamide drugs, penicillin and other synthetic and semi-synthetic antibiotics by the end of World War II, however, shifted the focus away from plant-based medicines towards single-ingredient synthetic compounds and relegated pharmacognosy (the study of drugs derived primarily from plants) to the vestiges of pharmacy college curricula past.
Citing Brinckmann et al. published in HerbalGram, Dr. Gurley noted that “by 1960, many botanicals and their officinal preparations that had enjoyed lengthy tenures in both the USP and USD were finally ‘dismissed’ due to a lack of usage among pharmacists and physicians.”
Resurrected from ‘the dustbin of medical history’
With the passage of DSHEA, herbs and other botanicals became wrapped up and encoded in the definition of dietary supplements along with vitamins, minerals, amino acids and dietary substances intended to supplement the diet (or any concentrates, metabolites, constituents, extracts or combinations of the above).
A group called the European-American Phytomedicines Coalition (EAPC) had been pushing for the creation of a separate OTC category for botanical drugs in the lead up to 1994, but this was met by resistance from a U.S. Food and Drug Administration that did not see a place for natural products in the modern drug review system at the time, Loren Israelsen, founder and president of the United Natural Products Alliance and co-founder of the EAPC, previously told NutraIngredients-USA.
“The implementation of DSHEA resurrected botanical extracts from the dustbin of medical history, transforming them from traditional tinctures and elixirs into contemporary dosage forms like capsules and tablets,” Dr. Gurley wrote. “One concerning aspect of DSHEA, which hinted at the emergence of various future health issues aligned with this revival, was its leniency toward regulatory oversight of botanical dietary supplements (BDS).”
As botanical formulations began to flood the market, they were now regulated like their supplement contemporaries, enjoying entry without the pre-market approval required of conventional drug products despite their phytomedicine past and phytochemical components.
“The mass influx of BDS onto both U.S. and global markets brought with it apprehensions regarding possible BDS-mediated drug interactions,” Dr. Gurley noted, adding that concerns were realized in 2000 when St. John’s wort (Hypericum perforatum), used as an antidepressant, interacted with immunosuppressant drug cyclosporine, causing acute rejection in heart transplant patients.
He suggested substantial potential for herb-drug interactions, referring to surveys showing that 20% to 30% of prescription drug users co-ingest medications and herbal supplements and that 70% of BDS users also take prescription medications. Moreover, older adults (40% to 70% of whom report regular use of herbal products) face increased odds of polypharmacy and age-related changes in drug disposition.
“Polypharmacy coupled with BDS usage, along with a hesitancy toward acknowledging such practices, place senior citizens at increased risk for HDI,” Dr. Gurley added.
Clinically relevant interactions
Herb-drug interactions currently fall into one of two categories: pharmacodynamic (interactions between phytochemicals and conventional medications at the drug receptor level) and the more prevalent pharmacokinetic (stemming from BDS-mediated alterations in human drug metabolism and/or transport.)
In the case of St. John’s wort, one of the more studied botanicals in the world, the pharmacokinetic interactions are tied to its hyperforin compound, which Dr. Gurley identified as “a double-edged phytochemical sword” that inhibits broad-based neurotransmitter reuptake as an anti-depressant but enhances systemic clearance for more than 70% of all prescription medications.
Other botanicals on the paper’s clinically relevant pharmacokinectic HDI list: goldenseal (Hydrastis canadensis), black pepper (Piper nigrum), Schisandra spp., Berberis spp., Coptis spp. and more recently cannabidiol. Green tea (Camellia sinensis), resveratrol and quercetin are flagged as posing low to intermediate risks primarily due to the limited number of studies designed to validate clinical relevance rather than therapeutic consequences of herb-drug interaction.
Regarding pharmacodynamic interactions, the review summarized a history of effects investigated in ephedra, ephedra-free supplements (proprietary blends) and licorice root (Glycyrrhiza glabra).
The current knowledge gap
“From the few summaries outlined above, the paucity of clinically relevant HDI candidates identified over the past 30 years is quite surprising, given the burgeoning BDS market,” Dr. Gurley wrote. “It appears, however, that highly popular, more familiar BDS like black cohosh, curcumin, echinacea, garlic, ginseng, kava kava, milk thistle, saw palmetto, valerian and many others harbor phytoconstituents that may be either inactive pharmacodynamically or ineffective pharmacokinetically.”
He also proposed factors at play ranging from phytochemical properties that hinder dissolution to lapses in adherence to current good manufacturing practices (e.g., proper characterization and verification, prevention of adulteration and contamination, assurance of dosage form performance, proper product label claims).
The review called attention to the unknowns and under-researched such as the impact of novel delivery systems designed to boost phytochemical absorption on HDI risk status and the “lamentably lacking” scientific awareness of most pharmacists and physicians regarding BDS and HDI despite reports and books dedicated to the topic. There is also the consideration whether HDI studied in vivo translate to humans.
“Fortunately, for physicians and pharmacists, the current risk for clinically relevant HDI seems fairly low; however, the vast majority of BDS have yet to be properly evaluated, and in all likelihood they never will,” Dr. Gurley concluded. “Nonetheless, when it comes to the co-ingestion of prescription medications and BDS, consumers and healthcare providers alike should always err on the side of caution.”
Source: Journal of Dietary Supplements
doi: 10.1080/19390211.2024.2327544
“Clinically Relevant Herb–Drug Interactions: A 30-Year Historical Assessment”
Author: Bill J. Gurley
