Development and Validation of a GC-FID Method for the Quantitation of Δ 8-Tetrahydrocannabinol and Impurities Found in Synthetic Δ 8-Tetrahydrocannabinol and Vaping Products.

Concerns about health hazards associated with the consumption of trans-delta-8-tetrahydrocannabinol products were highlighted in public health advisories from the U. S. Food and Drug Administration and U. S. Centers for Disease Control and Prevention. Simple and rapid quantitative methods to determine trans-delta-8-tetrahydrocannabinol impurities are vital to analyze such products. In this study, a gas chromatography-flame ionization detection method was developed and validated for the determination of delta-8-tetrahydrocannabinol and some of its impurities (recently published) found in synthesized trans-delta-8-tetrahydrocannabinol raw material and included olivetol, cannabicitran, Δ 8-cis-iso-tetrahydrocannabinol, Δ 4-iso-tetrahydrocannabinol, iso-tetrahydrocannabifuran, cannabidiol, Δ 4,8-iso-tetrahydrocannabinol, Δ 8-iso-tetrahydrocannabinol, 4,8-epoxy-iso-tetrahydrocannabinol, trans-Δ 9-tetrahydrocannabinol, 8-hydroxy-iso-THC, 9α-hydroxyhexahydrocannabinol, and 9ß-hydroxyhexahydrocannabinol. Validation of the method was assessed according to the International Council for Harmonization guidelines and confirmed linearity with R2 ≥ 0.99 for all the target analytes. The limit of detection and limit of quantitation were 1.5 and 5 µg/mL, respectively, except for olivetol, which had a limit of detection of 3 µg/mL and a limit of quantitation of 10 µg/mL. Method precision was calculated as % relative standard deviation and the values were less than 8.4 and 9.9% for the intraday precision and inter-day precision, respectively. The accuracy ranged from 85 to 118%. The method was then applied to the analysis of 21 commercially marketed vaping products claiming to contain delta-8-tetrahydrocannabinol. The products analyzed by this method have various levels of these impurities, with all products far exceeding the 0.3% of trans-Δ 9-tetrahydrocannabinol limit for hemp under the Agriculture Improvement Act of 2018. The developed gas chromatography-flame ionization detection method can be an important tool for monitoring delta-8-tetrahydrocannabinol impurities in commercial products.

Development and Validation of a Species-specific PCR Method for the Identification of Ginseng Species Using Orthogonal Approaches.

When testing botanical ingredients of herbal medicines and dietary supplements, the complexity of botanical matrixes often requires the use of orthogonal methods to establish identification procedures suitable for quality control purposes. Genomic-based botanical identification methods are evolving and emerging as useful quality control tools to complement traditional morphological and chemical identification methods. Species-specific polymerase chain reaction methods are being evaluated for botanical quality control and as a cost-effective approach to identify and discriminate between closely related botanical species. This paper describes orthogonal identification of Panax ginseng, P. quinquefolius, and P. notoginseng materials in commerce as an example of the development and validation of a set of species-specific polymerase chain reaction methods to establish botanical identity in ginseng roots. This work also explored the possibility of extending the application of species-specific polymerase chain reaction methods to provide species identity information for processed materials, such as steamed roots and hydroalcoholic extracts, and showed success with this approach. Finally, the paper provides recommendations for an out-of-specification investigation of samples that may pass some of the orthogonal tests and fail others.

Cannabis Inflorescence for Medical Purposes: USP Considerations for Quality Attributes.

There is an active and growing interest in cannabis female inflorescence (Cannabis sativa) for medical purposes. Therefore, a definition of its quality attributes can help mitigate public health risks associated with contaminated, substandard, or adulterated products and support sound and reproducible basic and clinical research. As cannabis is a heterogeneous matrix that can contain a complex secondary metabolome with an uneven distribution of constituents, ensuring its quality requires appropriate sampling procedures and a suite of tests, analytical procedures, and acceptance criteria to define the identity, content of constituents (e.g., cannabinoids), and limits on contaminants. As an independent science-based public health organization, United States Pharmacopeia (USP) has formed a Cannabis Expert Panel, which has evaluated specifications necessary to define key cannabis quality attributes. The consensus within the expert panel was that these specifications should differentiate between cannabis chemotypes. Based on the secondary metabolite profiles, the expert panel has suggested adoption of three broad categories of cannabis. These three main chemotypes have been identified as useful for labeling based on the following cannabinoid constituents: (1) tetrahydrocannabinol (THC)-dominant chemotype; (2) intermediate chemotype with both THC and cannabidiol (CBD); and (3) CBD-dominant chemotype. Cannabis plants in each of these chemotypes may be further subcategorized based on the content of other cannabinoids and/or mono- and sesquiterpene profiles. Morphological and chromatographic tests are presented for the identification and quantitative determination of critical constituents. Limits for contaminants including pesticide residues, microbial levels, mycotoxins, and elemental contaminants are presented based on toxicological considerations and aligned with the existing USP procedures for general tests and assays. The principles outlined in this review should be able to be used as the basis of public quality specifications for cannabis inflorescence, which are needed for public health protection and to facilitate scientific research on cannabis safety and therapeutic potential.

Regulatory landscape of dietary supplements and herbal medicines from a global perspective.

The number of Individuals that use dietary supplements and herbal medicine products are continuous to increase in many countries. The context of usage of a dietary supplement varies widely from country-to-country; in some countries supplement use is just limited to general health and well-being while others permit use for medicinal purposes. To date, there is little consensus from country to country on the scope, requirements, definition, or even the terminology in which dietary supplement and herbal medicines categories could be classified. Transparent science-based quality standards for the ingredients across these regulatory frameworks/definitions becomes even more important given the international supply chain. Meanwhile, there has been a rapid advancement in emerging technologies and data science applied to the field. This review was conceived at the Global Summit on Regulatory Sciences that took place in Beijing on September 2018 (GSRS2018) which is organized by Global Coalition for Regulatory Science Research (GCRSR) that consists of the global regulatory agencies from over ten countries including the European Union. This review summarizes a significant portion of discussions relating to a longitudinal comparison of the status for dietary supplements and herbal medicines among the different national jurisdictions and to the extent of how new tools and methodologies can improve the regulatory application.

A U.S. Pharmacopeia (USP) overview of Pan American botanicals used in dietary supplements and herbal medicines.

The United States Pharmacopeial Convention (USP) is a nonprofit, scientific, standard-setting organization, and world leader in establishing quality, purity, and testing standards for medicines, foods, and dietary supplements. USP quality standards are used in more than 140 countries and are legally recognized by more than 40 countries. Currently, there is renewed interest in herbal medicines globally, and health policies are being implemented worldwide for the use of complementary and traditional medicine. In response, USP has developed a robust body of monographs that can be used to guide industry and regulators in ensuring the quality and safety of botanical ingredients used in dietary supplements and herbal medicines. Throughout the Pan American regions, there is a strong tradition of using botanicals as herbal medicines and, as in other regions, a growing desire for botanical dietary supplements. This underscores the need for public quality standards to ensure quality, reduce the flow of substandard and adulterated products, and ensure public health and safety. In April 2022, USP launched the Pan America Botanical Dietary Supplements and Herbal Medicines Expert Panel, with experts representing 12 different countries. The Expert Panel's work focuses on developing quality control standards for the most important botanical ingredients used in the respective countries, ingredients that are also of global importance. This article provides an overview of the state of botanical dietary supplements and herbal medicines in different Pan American regions with a focus on the regulatory status of herbal products, the development of national quality and research initiatives, and policies related to agriculture conservation and sustainability, among other topics.

Lack of the T cell-specific alternative p38 activation pathway reduces autoimmunity and inflammation.

Stimulation via the T-cell receptor (TCR) activates p38α and p38ß by phosphorylation of p38 Tyr-323 (p38(Y323)). Here we characterize knockin mice in which p38α and/or ß Tyr-323 has been replaced with Phe. We find that p38α accounts for two-thirds and p38ß the remainder of TCR-induced p38 activation. T cells from double knockin mice (p38αß(Y323F)) had defects in TCR-mediated proliferation and Th1 and Th17 skewing, the former corresponding with an inability to sustain T-bet expression. Introduction of p38α(Y323F) into Gadd45α-deficient mice, in which the alternative p38 pathway is constitutively active, reversed T-cell hyperproliferation and autoimmunity. Furthermore, p38αß(Y323F) mice had delayed onset and reduced severity of the inflammatory autoimmune diseases collagen-induced arthritis and experimental autoimmune encephalomyelitis. Thus, T cell-specific alternative activation of p38 is an important pathway in T-cell proliferation, Th skewing, and inflammatory autoimmunity, and may be an attractive tissue-specific target for intervention in these processes.

Pharmacopeial Standards for the Quality Control of Botanical Dietary Supplements in the United States.

Botanicals are among the fastest growing segments of the dietary supplement industry in the U.S. The Dietary Supplement Health and Education Act (DSHEA; Public Law 103-417 [Oct. 25, 1994]) provided a regulatory classification for the trade of numerous botanicals and botanically-derived products as dietary supplements. The global supply chain, the adoption of many botanicals that are also recognized as traditional medicines around the world as dietary supplement ingredients, and the differing recognition of the national and international pharmacopeias as sources for voluntary or mandatory quality standards present challenges in ensuring the quality of the ingredients and products. The complexity of quality assurance by compliance with pharmacopeial standards is illustrated in this article with a brief history of pharmacopoeias including their official recognition in national laws, their approaches to the science behind the standards, the use of reference standards for quality assessment and regulatory compliance, the use of pharmacopeial standards by the industry and regulators within the DSHEA framework in the United States, and a discussion of the global supply chain. Pharmacopeial standards can help regulators and the industry adapt to the new technologies that present both opportunities and challenges.

What Should Clinicians Know About Dietary Supplement Quality?

Increase in dietary supplement use in the United States suggests a great need for clinicians to be aware of the range of supplements' quality parameters. Regulatory requirements exist, but specific quality parameters for each ingredient are not set by regulators. This article considers how clinicians can evaluate dietary supplement product quality, assess manufacturers' adherence to public quality standards, and encourage use of verification and certification programs.

United States pharmacopeia safety evaluation of spirulina.

The Dietary Supplements Information Expert Committee (DSI-EC) of the United States Pharmacopeial Convention (USP) reviews the safety of dietary supplements and dietary supplement ingredients for the purpose of determining whether they should be admitted as quality monographs into the United States Pharmacopeia and National Formulary (USP-NF). The United States Food and Drug Administration (FDA) has enforcement authority to pursue a misbranding action in those instances where a dietary supplement product indicates that it conforms to USP standards but fails to so conform. Recently DSI-EC undertook a safety evaluation of spirulina, a widely used dietary ingredient. DSI-EC reviewed information from human clinical trials, animal studies, and regulatory and pharmacopeial sources and analyzed 31 adverse event reports regarding spirulina to assess potential health concerns. At the conclusion of this review, DSI-EC assigned a Class A safety rating for Spirulina maxima and S. platensis, thereby permitting the admission of quality monographs for these dietary supplement ingredients in USP-NF. DSI-EC continually monitors reports concerning the safety of dietary supplements and dietary supplement ingredients for which USP dietary supplement monographs are developed. The DSI-EC may revisit the safety classification of spirulina as new information on this dietary ingredient becomes available.

Multi-Criteria Decision Analysis Model for Assessing the Risk from Multi-Ingredient Dietary Supplements (MIDS).

Military personnel use dietary supplements (DS) for performance enhancement, bodybuilding, weight loss, and to maintain health. Adverse events, including cardiovascular (CV) effects, have been reported in military personnel taking supplements. Previous research determined that ingestion of multi-ingredient dietary supplements (MIDS), can lead to signals of safety concerns. Therefore, to assess the safety of MIDS, the Department of Defense via a contractor explored the development of a model-based risk assessment tool. We present a strategy and preliminary novel multi-criteria decision analysis (MCDA)-based tool for assessing the risk of adverse CV effects from MIDS. The tool integrates toxicology and other relevant data available on MIDS; likelihood of exposure, and biologic plausibility that could contribute to specific aspects of risk.Inputs for the model are values of four measures assigned based on the available evidence supplemented with the opinion of experts in toxicology, modeling, risk assessment etc. Measures were weighted based on the experts' assessment of measures' relative importance. Finally, all data for the four measures were integrated to provide a risk potential of 0 (low risk) to 100 (high risk) that defines the relative risk of a MIDS to cause adverse reactions.We conclude that the best available evidence must be supplemented with the opinion of experts in medicine, toxicology and pharmacology. Model-based approaches are useful to inform risk assessment in the absence of data. This MCDA model provides a foundation for refinement and validation of accuracy of the model predictions as new evidence becomes available.

Quality specifications for articles of botanical origin from the United States Pharmacopeia.

BACKGROUND: In order to define appropriate quality of botanical dietary supplements, botanical drugs, and herbal medicines, the United States Pharmacopeia (USP) and the Herbal Medicines Compendium (HMC) contain science-based quality standards that include multiple interrelated tests to provide a full quality characterization for each article in terms of its identity, purity, and content. PURPOSE: To provide a comprehensive description of the pharmacopeial tests and requirements for articles of botanical origin in the aforementioned compendia. Selective chromatographic procedures, such as high-performance liquid chromatography (HPLC) and high-performance thin-layer chromatography (HPTLC), are used as Identification tests in pharmacopeial monographs to detect species substitution or other confounders. HPLC quantitative tests are typically used to determine the content of key constituents, i.e., the total or individual amount of plant secondary metabolites that are considered bioactive constituents or analytical marker compounds. Purity specifications are typically set to limit the content of contaminants such as toxic elements, pesticides, and fungal toxins. Additional requirements highlight the importance of naming, definition, use of reference materials, and packaging/storage conditions. METHODS: Technical requirements for each section of the monographs were illustrated with specific examples. Tests were performed on authentic samples using pharmacopeial reference standards. The chromatographic analytical procedures were validated to provide characteristic profiles for the identity and/or accurate determination of the content of quality markers. RESULTS: The multiple tests included in each monograph complement each other to provide an appropriate pharmacopeial quality characterization for the botanicals used as herbal medicines and dietary supplements. The monographs provide detailed specifications for identity, content of bioactive constituents or quality markers, and limits of contaminants, adulterants, and potentially toxic substances. Additional requirements such as labeling and packaging further contribute to preserve the quality of these products. CONCLUSION: Compliance with pharmacopeial specifications should be required to ensure the reliability of botanical articles used for health care purposes.

Dietary supplements quality analysis tools from the United States Pharmacopeia.

The United States Food and Drug Administration (FDA) issued the dietary supplement (DS) current good manufacturing practice (GMP) regulations in compliance with the mandate from the Dietary Supplements Health and Education Act (DSHEA), with the intention of protecting public health by ensuring the quality of DS. The GMP regulations require manufacturers to establish their own quality specifications for identity, purity, strength, composition, and absence of contaminants. Numerous FDA-conducted GMP inspections found that the private specifications set by these manufacturers are often insufficient to ensure adequate quality of dietary ingredients and DS. Wider use of the public standards developed by the United States Pharmacopeial Convention (USP), in conjunction with GMP compliance, can help ensure quality and consistency of DS as they do for medicines. Public health protection could be enhanced by strengthening the GMP provisions to require conformance with relevant United States Pharmacopeia-National Formulary (USP-NF) standards, or in the absence of USP standards, other public compendial standards. Another serious concern is the presence of synthetic drugs and drug analogues in products marketed as DS. Use of the new USP General Chapter Adulteration of Dietary Supplements with Drugs and Drug Analogs <2251> may reduce the exposure of consumers to dangerous drugs disguised as DS. Copyright © 2016 John Wiley & Sons, Ltd.

Safety and performance benefits of arginine supplements for military personnel: a systematic review.

CONTEXT: Dietary supplements are widely used by military personnel and civilians for promotion of health. OBJECTIVE: The objective of this evidence-based review was to examine whether supplementation with l-arginine, in combination with caffeine and/or creatine, is safe and whether it enhances athletic performance or improves recovery from exhaustion for military personnel. DATA SOURCES: Information from clinical trials and adverse event reports were collected from 17 databases and 5 adverse event report portals. STUDY SELECTION: Studies and reports were included if they evaluated the safety and the putative outcomes of enhanced performance or improved recovery from exhaustion associated with the intake of arginine alone or in combination with caffeine and/or creatine in healthy adults aged 19 to 50 years. DATA EXTRACTION: Information related to population, intervention, comparator, and outcomes was abstracted. Of the 2687 articles screened, 62 articles meeting the inclusion criteria were analyzed. Strength of evidence was assessed in terms of risk of bias, consistency, directness, and precision. RESULTS: Most studies had few participants and suggested risk of bias that could negatively affect the results. l-Arginine supplementation provided little enhancement of athletic performance or improvements in recovery. Short-term supplementation with arginine may result in adverse gastrointestinal and cardiovascular effects. No information about the effects of arginine on the performance of military personnel was available. CONCLUSIONS: The available information does not support the use of l-arginine, either alone or in combination with caffeine, creatine, or both, to enhance athletic performance or improve recovery from exhaustion. Given the information gaps, an evidence-based review to assess the safety or effectiveness of multi-ingredient dietary supplements was not feasible, and therefore the development of a computational model-based approach to predict the safety of multi-ingredient dietary supplements is recommended.

Evidence-based evaluation of potential benefits and safety of beta-alanine supplementation for military personnel.

This Department of Defense-sponsored evidence-based review evaluates the safety and putative outcomes of enhancement of athletic performance or improved recovery from exhaustion in studies involving beta-alanine alone or in combination with other ingredients. Beta-alanine intervention studies and review articles were collected from 13 databases, and safety information was collected from adverse event reporting portals. Due to the lack of systematic studies involving military populations, all the available literature was assessed with a subgroup analysis of studies on athletes to determine if beta-alanine would be suitable for the military. Available literature provided only limited evidence concerning the benefits of beta-alanine use, and a majority of the studies were not designed to address safety. Overall, the strength of evidence in terms of the potential for risk of bias in the quality of the available literature, consistency, directness, and precision did not support the use of beta-alanine by military personnel. The strength of evidence for a causal relation between beta-alanine and paresthesia was moderate.

Assessing safety of herbal products for menopausal complaints: an international perspective.

Future research of herbal products for menopausal women should include long-term safety assessments because women may use these products for prolonged periods of time. Growing numbers of women take prescription medications and concurrently use herbal products for alleviation of menopausal symptoms. Because of possible herb-drug interactions, both drug and supplement manufacturers should provide basic pharmacokinetic data to reduce the risk of adverse interactions. In addition, herbal products produced to high quality standards are essential for ensuring consumer safety. Regulatory frameworks must be in place to ensure that herbal ingredients' identities have been verified, that they have been properly quantified per unit dose, that the product is within tolerance limits for contaminants, that the product's safety and effectiveness under the recommended conditions of use have been assessed before sale to the public, and that a system is in place to detect and deal with adverse reactions when they arise. This article explores these and related concerns.