Bill J. Gurley

Softgel capsules are widely used in dietary supplements to deliver lipophilic ingredients, including essential and fixed oils. This study evaluated the disruption behavior of 104 commercially available softgel formulations under biorelevant conditions designed to approximate the gastrointestinal environment. Products were categorized as essential oil-containing (n = 40), fixed oil-containing (n = 48), combination (n = 6), and cannabidiol (CBD)-containing (n = 10) formulations. Disruption testing was conducted in biorelevant media, with enzyme supplementation applied according to shell composition when predefined rupture criteria were not achieved. Essential oil-containing softgels exhibited significantly lower pass rates than fixed oil formulations (35% vs 94%, χ², p < 0.0001). Shell composition also affected outcomes, as gelatin-based systems demonstrated higher overall pass rates than vegetable-based shells (77% vs 26%, χ², p < 0.0001). A partial rupture-resealing phenomenon characterized by transient fissuring and formation of a persistent hydrated pellicle was observed in certain products. Lot-to-lot variability was identified among selected formulations. These findings indicate that fill composition, shell material, and manufacturing variables contribute to disruption variability in dietary supplement softgels. Evaluation under physiologically informed testing conditions may reveal performance differences not evident under conventional water-based methods and may be particularly relevant for essential oil-containing formulations.

Curcumin-containing dietary supplements are widely marketed with claims of enhanced bioavailability, despite well-recognized limitations related to poor aqueous solubility, chemical instability, and extensive first-pass metabolism. Comparisons among commercially available products using physiologically relevant performance metrics remain limited. To systematically evaluate disintegration, dissolution, and bioaccessibility of curcuminoids and (S)-ar-turmerone from a cross section of commercially available turmeric dietary supplements under fasted- and fed-state biorelevant conditions. Eight marketed turmeric supplements representing diverse formulation strategies were assessed for disintegration and dissolution using USP-aligned methods in fasted- and fed-state simulated gastric and intestinal media (FaSSGF, FaSSIF, FeSSGF, FeSSIF). Bioaccessible concentrations, quantities, and dose fractions of curcuminoids and (S)-ar-turmerone were quantified after 3 h. All products exhibited poor dissolution overall, with no formulation achieving greater than 40% total release. Dissolution was lowest under fasted-state conditions and improved modestly in fed-state gastric media, reflecting the influence of lipid content. Products with higher curcuminoid loads per capsule generated greater absolute bioaccessible concentrations despite poor release efficiency, whereas a phytosome formulation achieved superior release despite a lower dose. Several products marketed as "enhanced" formulations demonstrated poor disintegration and low bioaccessibility. These findings indicate that bioaccessible concentration is governed jointly by dosage-form performance and curcuminoid dose loading, and that plasma exposure metrics dominated by conjugated metabolites may not reliably reflect formulation performance. Commercial turmeric supplements exhibit substantial limitations in biorelevant disintegration and dissolution. Superior in vitro release is a prerequisite - but not a guarantee - for enhanced systemic exposure, underscoring the need for cautious interpretation of bioavailability claims.

Botanical supplements, herbal remedies, and plant-derived products are used globally. However, botanical dietary supplements are rarely subjected to robust safety testing unless there are adverse reports in post-market surveillance. Botanicals are complex and difficult to assess using current frameworks designed for single constituent substances (e.g. small molecules or discrete chemicals), making safety assessments costly and time-consuming. The liver is a primary organ of concern for potential botanical-induced hepatotoxicity and botanical-drug interactions as it plays a crucial role in xenobiotic metabolism. The NIH-funded Drug Induced Liver Injury Network noted that the number of botanical-induced liver injuries in 2017 nearly tripled from those observed in 2004-2005. New approach methodologies (NAMs) can aid in the rapid and cost-effective assessment of botanical supplements for potential hepatotoxicity. The Hepatotoxicity Working Group within the Botanical Safety Consortium is working to develop a screening strategy that can help reliably identify potential hepatotoxic botanicals and inform mechanisms of toxicity. This manuscript outlines the Hepatotoxicity Working Group's strategy and describes the assays selected and the rationale for the selection of botanicals used in case studies. The selected NAMs evaluated as a part of this effort are intended to be incorporated into a larger battery of assays to evaluate multiple endpoints related to botanical safety. This work will contribute to a botanical safety toolkit, providing researchers with tools to better understand hepatotoxicity associated with botanicals, prioritize and plan future testing as needed, and gain a deeper insight into the botanicals being tested.

Since its establishment in 1994, the National Center for Natural Products Research (NCNPR) at the University of Mississippi has made notable contributions to the field of natural product research, coinciding with the passage of the Dietary Supplement Health and Education Act. Over the past three decades, the Center has focused on studying plants, herbs, and other natural materials for applications in medicine, agriculture, and nutraceuticals, particularly in the area of botanical dietary supplements. NCNPR scientists have been actively engaged in developing and improving quality control measures to help ensure the safety of dietary supplements in response to a growing market. The Center's research efforts have led to its designation as a U.S. Food and Drug Administration Center of Excellence, reflecting its role in advancing scientific understanding of natural products. Through collaborations with various stakeholders and regulators, NCNPR has contributed to shaping the regulatory landscape for botanical dietary supplements, highlighting both their potential health benefits and associated risks, such as product adulteration. The Center's influence is also evident internationally, as demonstrated by its annual International Conference on the Science of Botanicals, which will mark its 26th year in April 2025. This overview outlines NCNPR's role in supporting research, regulation, and safety in the natural products field.

The Dietary Supplement Health and Education Act, a legislative measure ushering in a novel class of complementary healthcare products known as dietary supplements, will mark its 30th anniversary in October 2024. Over this 30-year period, dietary supplement usage 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 that are now regular staples in the American healthcare system and used by half of all U.S. consumers. One of the fastest-growing segments of the dietary supplement market during this 3-decade interval has been those products formulated with botanical extracts. Coincident with the growing popularity of botanical dietary supplements (BDS) has been their concomitant ingestion with conventional prescription medications. BDS are complex mixtures of phytochemicals oftentimes exhibiting complex pharmacology. Formulated as concentrated phytochemical extracts, BDS are vehicles for a host of plant secondary metabolites rarely encountered in the typical diet. When taken with prescription drugs, BDS may give rise to clinically significant herb-drug interactions (HDI). Pharmacodynamic HDI describe interactions between phytochemicals and conventional medications at the drug receptor level, while pharmacokinetic HDI stem from phytochemical-mediated induction and/or inhibition of human drug metabolizing enzymes and/or transporters. This review summarizes BDS identified over the last 30 years that pose clinically relevant HDI and whose mechanisms are either pharmacodynamically or pharmacokinetically mediated.

A successful randomized clinical trial of the effect of dietary supplements on a chosen endpoint begins with developing supporting data in preclinical studies while paying attention to easily overlooked details when planning the related clinical trial. In this perspective, we draw on our experience studying the effect of an ethanolic extract from Artemisia dracunculus L. (termed PMI-5011) on glucose homeostasis as a potential therapeutic option in providing resilience to metabolic syndrome (MetS). Decisions on experimental design related to issues ranging from choice of mouse model to dosing levels and route of administration in the preclinical studies will be discussed in terms of translation to the eventual human studies. The more complex considerations in planning the clinical studies present different challenges as these studies progress from testing the safety of the dietary supplement to assessing the effect of the dietary supplement on a predetermined clinical outcome. From the vantage point of hindsight, we will outline potential pitfalls when translating preclinical studies to clinical studies and point out details to address when designing clinical studies of dietary supplements.

Cannabidiol (CBD) is a biologically active, non-psychotropic component of Cannabis sativa whose popularity has grown exponentially in recent years. Besides a wealth of potential health benefits, ingestion of CBD poses risks for a number of side effects, of which hepatotoxicity and CBD/herb-drug interactions are of particular concern. Here, we investigated the interaction potential between the cannabidiol-rich cannabis extract (CRCE) and methylsulfonylmethane (MSM), a popular dietary supplement, in the mouse model. For this purpose, 8-week-old male C57BL6/J mice received MSM-containing water (80 mg/100 mL) ad libitum for 17 days. During the last three days of treatment, mice received three doses of CRCE administered in sesame oil via oral gavage (123 mg/kg/day). Administration of MSM alone did not result in any evidence of liver toxicity and did not induce expression of mouse cytochrome P450 (CYP) enzymes. Administration of CRCE did produce significant (p < 0.05) increases in Cyp1a2, Cyp2b10, Cyp2c29, Cyp3a4, Cyp3a11, Cyp2c65, and Cyp2c66 messenger RNA, however, this effect was not amplified by MSM/CRCE co-treatment. Similarly, no evidence of liver toxicity was observed in MSM/CRCE dosed mice. In conclusion, short-term MSM/CRCE co-administration did not demonstrate any evidence of hepatotoxicity in the mouse model.

The proliferation in the last few years of cannabidiol (CBD)-containing products in the U.S. markets has been greatly accelerated by changes in the regulatory environment, and by perceptions of their health benefits and presumed safety. The result has been aggressive marketing of many types of products, some of dubious quality, making or implying drug-type claims. The recent approval by the U.S. Food and Drug Administration (FDA) of CBD in the form of Epidiolex®, further complicates the regulatory picture. In addition, a number of studies suggest that, at least at high doses, there may be serious adverse effects or drug interactions associated with CBD. At present, CBD-containing products do not meet the strict definition of dietary supplements, but the FDA is continuing to consider some framework under which they might be allowed. Meanwhile, FDA has adopted a “risk-based” enforcement policy. Possible approaches to a new framework for regulation of CBD products as dietary supplements are discussed here, including expanded research emphasis, a robust corporate stewardship program, and a rigorous adverse event reporting program.

Products containing cannabidiol (CBD) are now available throughout the United States, but their quality is oftentimes questionable. The CBD and Δ⁹-tetrahydrocannabinol (THC) content of 25 commercially available hemp oil products, obtained throughout the state of Mississippi, was determined via gas chromatography/flame ionization detection (GC/FID). These products were also analyzed for the presence of synthetic cannabinoids using full scan gas chromatography/mass spectrometry (GC/MS). Analytical findings were compared to label claims for CBD content. Product label claims for CBD ranged from no claim to 500 mg per serving; however, marked variability was observed between actual CBD content and claimed quantities. Of the 25 products, only three were within ±20% of label claim. Fifteen were well below the stated claim for CBD; two exceed claims in excess of 50%; and 5 made no claims. In addition, THC content for three products exceeded the 0.3% legal limit. Furthermore, four products—primarily marketed for vaping—were adulterated with synthetic cannabinoids. From this small, but diverse, sampling of hemp-derived merchandise, it appears that most product label claims do not accurately reflect actual CBD content and are fraudulent in that regard. Moreover, products that exceed legal THC levels may jeopardize a consumer’s employment status (i.e. failed “drug test”), while those adulterated with synthetic cannabinoids may subject them to serious adverse health effects. These findings argue strongly for further development of current good manufacturing practices for CBD-containing products and their stringent enforcement.