Last fall, at a moment of both scientific momentum and policy transition, more than 140 researchers, from the National Institutes of Health (NIH), and other stakeholders from around the world logged into the 2025 CARBON Virtual Symposium. The CARBON program continues to occupy a distinctive niche within the NIH. This program includes an NIH-supported consortium of research centers and linked pilot project awards, jointly led by the NIH’s Office of Dietary Supplements (ODS) and National Center for Complementary and Integrative Health (NCCIH), with participation by other NIH components, most recently including the National Institute on Aging and the National Institute on Drug Abuse (NIDA).
While most natural products research in the US, including that supported by NIH, focuses on purified or semi-purified chemicals, the CARBON differs in its support for transdisciplinary, translational research on chemically complex botanical interventions. Moving away from a focus on isolating “the” active compound from a promising natural product (NP). This improved approach has supported publications on methods for elucidating interactions between NP constituents and the functional contributions of multiple constituents within a biologically active NP, forming the basis for enhanced quality control of product use in clinical applications and increased reproducibility.
2025 NIH Carbon Program
The 2025 symposium showcased not only the progress of individual centers but also the evolving NIH environment for supporting botanical and NP research. The first day began with a keynote lecture and showcased recent and planned CARBON and related research, while the second day focused on the NIH context.
Dr. Stephen Barnes (University of Alabama, Birmingham) provided a wide-ranging keynote lecture briefly touching on multiple lessons from his lifetime of research on NP and metabolomics. Barnes pointed to the importance of transdisciplinary collaborations to understand the health effects of botanical products and emphasized the crucial contribution of the natural product integrity process, initiated by NCCIH and adopted by ODS to improve the replicability of NP research and safety of NP consumption. . He highlighted the evolution of product use for healthcare in humans, beginning with those that occur naturally and continuing on to synthetic pharmaceuticals, many noted to be present in wastewater. Projecting out into the cosmos, he concluded with NP research questions that may be critical to answer for the support of humans in a future era of interplanetary travel.
The Center on Botanicals Enhancing Functional Resilience in Aging (BENFRA) presented new translational data on Centella asiatica and Withania somnifera showing that mice consuming a hot water extract of Centella were resilient to decreases in some aspects of memory and learning. Females, but not males, also showed increased resilience to anxiety-like behavior. Fruit flies (Drosophila melanogaster) that were fed the extract for two weeks showed resilience to age-related decreases in motility and phototaxis. The BENFRA research team has applied their trans-disciplinary expertise in sleep, aging, and the neuronal bases of cognition and pharmacognosy to generate and publish evidence that the caffeoylquinic acids and triterpenes in Centella each contribute differently to each of these outcomes (Nutrients. 2023. 15:4016; Frontiers in Aging. 2024; Nutrients. 2025. 17:3171). Similarly, BENFRA studies in aging Drosophila suggest that resilience provided by Withania somnifera root extracts to sleep and mood changes may be mediated by withanolide and alkaloidal compounds respectively (Nutrients. 2022; J Ethnopharmacol. 2025. 357:120905.) The BENFRA team is now using the Centella extract used in the mechanistic studies in a (separately supported) Phase I biomarker clinical trial for mild cognitive impairment (NCT05591027).
Centella asiatica and Withania somnifera , Wikipedia.
Four R03 grant funded CARBON pilot projects, associated with the BENFRA Center, supported career development for faculty at institutions with lower levels of NIH support while complementing the BENFRA research. These included pilot projects studying: the effects of the Centella extract on inflammaging in Drosophila; the development of a proton spin network fingerprint library to facilitate the analysis of Centella compounds (J Nat Prod. 2025. 88:975); the effects of digestive fluids on Withania somnifera extracts and the effects of Withania somnifera extracts on drug metabolizing enzymes (Drug Metab Dispos. 2025 53:100024 and J Diet Suppl. 2025. 22:613).
The Icahn Mount Sinai and Rutgers Center shared a mechanistic immune system-brain interactions model for their grape polyphenol preparation (BDPP), including immune modulation, reduced neuroinflammatory signatures, and stress resilience effects. Data from a completed 84 participant Phase I trial (NCT04421079) is undergoing analysis..
The Immulina project (University of Mississippi and University of Tennessee Health Science Center)published on the effects of Immulina, a Limnospira fusiformis extract, on viral load, body weight maintenance, and immune responses in a mouse model. In this study, Immulina,, was provided at different times relative to an experimental influenza infection (Phytomedicine. 2024. 132:155588 and 155778). Mechanistic mouse studies showed effects on inflammatory cytokine production in bone marrow-derived dendritic cells and macrophages (Planta Med. 2023. 89:1483). An ongoing human biomarker trial (NCT05447078) to determine the optimal dose range and assessment timing of immune biomarker response was scheduled for completion in December 2025.
The High-Content Functional Annotation of Natural Products Center (HiFAN; UC Santa Cruz, Simon Fraser University and University of North Carolina Greensboro) and the Natural Products Magnetic Resonance Database (NP-MRD; Pacific Northwest National Lab and colleagues) presented publicly available analytical resources they have developed. The HiFAN methodological pipeline supports the prediction of biomolecular and/or cellular activities of chemically complex NPs and the active responsible constituents, both individually and via interactions (J Chemom. 2024. 38(6):e3531). The methodology can be applied to a wide variety of biological outcomes and is compound- and outcome-agnostic. A botanical-focused MS2 spectral library, Library Enabling Annotation of Botanical Natural Products (LEAFBot), was built to improve annotation of botanical samples. It contains experimental spectra for more than 300 purified plant secondary metabolites, many not found in existing public databases. The data are housed within the Global Natural Products Social Molecular Networking Ecosystem which enables more accurate identification of unknown spectral features and reduces false positives in metabolomic workflows (J Am Soc Mass Spectrum. 2025. 36:926-929.).
The NP-MRD is now the world’s largest resource for NP NMR data, containing NMR spectra of close to 300,000 experimental and simulated spectra with approximately five million predicted spectra for almost 300,000 NP compounds. The database includes compound source (taxonomy/species) information for all compounds in the database, as well as information on compounds’ physico-chemical characteristics and 3-D structures. A range of raw data formats are accommodated. In addition to tools for spectral and structure visualization and similarity search functions, each compound information page in the NP-MRD includes links to other databases such as DrugBank, Phenol Explorer, FoodDB, KNApSAcK, Chemspider, KEGG, PubChem, PDB and Good Scents. The platform has implemented major upgrades to the deposition system, spectral search speed, and prediction capabilities that have driven increases in annual data submissions and continued to broaden the user base. NP-MRD represents a high value resource for ensuring fair data sharing and reproducibility across interdisciplinary research fields (Nucleic Acids Research. 2025. 53:D700) and satisfies US National Institutes of Health’s guidelines for data sharing repositories.
Although not part of the CARBON, the Natural Products Drug Interactions (NaPDI) Research Center (Washington State University), an independent NCCIH Center of Excellence, collaborated closely with several CARBON investigators. Like the CARBON centers, the NaPDI Center focuses on contributions of multiple chemical constituents within the NP being studied. The center reported clinical and physiologically-based pharmacokinetic-modeling insights on potential and often clinically observed drug interactions involving kratom, goldenseal, hemp, and oregano. The NaPDI Center recently completed the first clinical evaluation of a goldenseal-metformin interaction in patients with type 2 diabetes, finding no clinically meaningful effect on therapeutic effect despite decreases in metformin exposure at lower metformin doses. The investigators emphasized the importance of measuring both pharmacokinetics and clinical biomarkers in herb-drug interaction studies (Clin Transl Sci. 2025. 18(2):e70120).
Triterpene, compound found in Centella asiatica, Wikipedia.
The newly awarded BlueBIOME translational research team (Colorado State University, Florida State University and University of Utah) will study how the gut microbiome shapes blueberry polyphenol metabolism and vascular outcomes, developing computational tools to predict individual “metabotypes.” The goals for this newly funded CARBON team include the development of: 1) publicly available databases of gut microbial species and microbial enzymes that participate in polyphenol metabolism; and 2)machine learning tools that can advance our understanding of the mechanisms and determinants of physiologic responses to a broad range of phytochemicals. Both of which could inform the design of future clinical trials of the effects of fruits and vegetables and their constituents on health. Eventually providing data that might support precision nutrition.
Over the last five years of CARBON funding, in addition to the essential transdisciplinary collaborations within each center, collaborations between CARBON centers produced new knowledge that could not have been developed by the individual projects had they remained siloed. This included the translational research centers that collaborated with Hi-FAN to survey their products for potential additional active compounds or activities, thus providing beta-testing for the Hi-FAN methodological pipeline. The Hi-FAN COVID paper, a collaboration with virology experts (Khadilkar, et al., J Nat Prod. 2023) and the highly collaborative (8-team) Hi-FAN-led collaboration to assess pitfalls and good practices in untargeted HPLC-MS analysis of chemically complex NPs (Houriet, et al., Anal Chem. 2025) were just two more notable collaborative successes.
This year’s meeting took place amid NIH-wide shifts in funding practices. Moving forward, NIH plans to significantly reduce the number of highly specific NOFOs and encourage greater use of broad parent announcements such as the parent R01 and R21. Beginning in late 2025, NIH’s new “Highlighted Topics” implement a greater focus on investigator-initiated science and broader and nimbler indications of areas of NIH scientific interest (see “Capital Communiques” in this issue for more information on these).
The second day of the symposium highlighted other NIH programs focused on NP research, including NIGMS technology development portfolios, NINDS translational mechanism research, and NCI’s integrative oncology efforts. Program officers emphasized how CARBON investigators can navigate these evolving funding mechanisms while aligning their work with complementary NIH initiatives and resources.
Despite the rapidly changing research funding landscape, CARBON investigators presented strong momentum, with the 2020-2025 cohort having already collectively published 77 research papers during their project periods to date and with two centers expecting to report clinical trial results in 2026. The centers have trained many early career scientists in their rigorous, transdisciplinary approach. All of these achievements, along with the Hi-FAN pipeline, the NMR database, and the herb-drug interaction studies database (https://napdicenter.org/) continue to strengthen NP research and demonstrate the public health importance of funding for NP research across NIH. As the landscape of NIH funding continues to evolve, CARBON investigators remain strongly positioned to contribute rigorous science and shared tools that advance the study of chemically complex botanicals and other NPs. The collaborative efforts among the CARBON centers highlight the resilience of this research community with their strong scientific foundation and great potential to continue advancing NP research.
