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Natural Products Research—Information for Researchers

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Definition

Natural products include a large and diverse group of substances from various natural sources such as plants, bacteria, fungi, insects, arachnids, marine organisms, and higher-order animals. The term “natural products” also refers to complex mixtures from these products and the isolated compounds derived from them. In addition, this NCCIH definition also includes vitamins, minerals, probiotics—i.e., live microorganisms, bacteria in most cases, that are intended to have health benefits—and special diets for medical conditions or health outcomes.

Natural products have a long history of use as drugs, drug precursors, and/or complementary health adjuvants. Such materials have provided the source or inspiration for a vast number of U.S. Food and Drug Administration (FDA)-approved agents and continue to be one of the major sources of inspiration for drug discovery. NCCIH will support research on all types of natural products as long as projects are within the scope of the Center’s research priorities and the product(s) can be linked to traditional medicine or other complementary and integrative health practices.

Priorities in Natural Products Research

1. Background and Approach

NCCIH 2016 Strategic Plan

Although many natural products are widely marketed and readily available to consumers as dietary supplements, strong evidence regarding their usefulness and safety does not uniformly exist. The NCCIH 2016 Strategic Plan emphasizes fundamental research to advance understanding of basic biological mechanisms of action of natural products, including prebiotics and probiotics. It also describes NCCIH’s interests in catalyzing advances in natural products research methodology and supporting clinical studies of the use of natural products for symptom management, well-being, and health promotion. The research strategies described in the Strategic Plan are intentionally broad and span a wide range of research approaches and methodologies.

NCCIH is particularly interested in identifying effective complementary health approaches for management of symptomatic conditions that are commonly treated in primary care—such as pain, sleep disturbance, and mild-to-moderate mental health conditions such as depression, anxiety, and posttraumatic stress. The Center is also interested in examining the effects of probiotics and other natural products on gut microbiome interactions with the nervous system, immune system, and/or other physiological systems.

A Research Pipeline

NCCIH’s overall philosophy for research on natural products can be represented as a pipeline. The entrance of the pipeline is very wide and represents basic research. It allows for exploratory efforts on many types of natural products and includes a wide variety of possible biological activities. The end of the pipeline is very narrow and represents late-stage clinical efficacy research. This is limited to a very small number of high-priority products and conditions.

NCCIH research priorities for most natural products are at the exploratory end of the research and development continuum. At this stage of research, NCCIH has broad interest in studying the biological activities of natural products, including studies in preclinical models for a wide variety of potential clinical indications. The development of new resources (e.g., as data or methodologies) and the leveraging of existing resources (e.g., for screening or assays) also have been of significant interest to the Center.

One of the foundational hypotheses of herbal medicine is that complex products contain a combination of compounds that are more effective and less toxic than any isolated constituent. However, to completely understand the activity of a complex product, it is necessary to identify the individual chemicals responsible for that activity and how they interact with each other in preclinical model systems. Therefore, NCCIH has interest in studying the isolated compounds as well as the complex mixtures from which they originate. This can also include discovery and characterization of new natural products.

Clinical Trials

Targeted development and large clinical trials will be warranted only when basic and translational research allows rigorous testing of evidence-based hypotheses. Importantly, NCCIH believes that maximally informative clinical efficacy studies of natural products should be based on a solid foundation of mechanistic research. Therefore, late-stage clinical efficacy research will necessarily be limited to those natural products with a substantial body of evidence in preclinical models.

Natural Product Integrity Policy

NCCIH is committed to the rigorous scientific investigation of natural products used in complementary and integrative health practices. The Center’s Natural Product Integrity Policy establishes guidance on the information required by NCCIH for different types of products used in both mechanistic and clinical research including complex botanical products, complex animal products, probiotics, refined products, and placebos.

Sufficient product information must be included in the application to allow the peer reviewers to evaluate the significance, feasibility, and scientific strength of the project. Investigators must demonstrate that their investigative team has the appropriate product and analytical expertise to select the test and placebo agents for study and to ensure product integrity. For example, botanists trained in taxonomy may be required to identify voucher specimens accurately. Experts in natural products chemistry, microbiology, food science, botany, pharmacognosy, analytical chemistry, etc., may need to be consulted to provide the analytic rigor with which to evaluate product composition. Applicants requesting funds to research natural products must review NCCIH’s guidance regarding required information.

2. Examples of High-Priority Topic Areas

NIH HEAL Initiative

NCCIH is an active participant in the NIH HEAL (Helping To End Addiction Long-termSM) Initiative, a trans-NIH effort to accelerate scientific solutions to stem the national public health crisis related to opioids. The Center works to identify and fund research in two priority areas outlined in the HEAL scientific research plan:

  • To improve treatments for opioid misuse and addiction through identifying new treatment options for addiction and optimizing effective existing therapies
  • To enhance pain management via improved understanding of chronic pain and developing new, nonaddictive pain treatments.

Visit nccih.nih.gov/grants/heal to see examples (which so far have been primarily studies of mind and body modalities) of NCCIH-led or co-led initiatives under HEAL.

Biological Mechanisms of Natural Products

Another top priority is to advance fundamental research to increase understanding of basic biological mechanisms of action of natural products. Recent, related Requests for Applications (RFAs) include:

  • RFA-AT-18-003, Discovery and Biological Signatures of Diet-Derived Microbial Metabolites (R01 Clinical Trial Optional)
  • RFA-AT-19-008, Exploring the Mechanisms Underlying Analgesic Properties of Minor Cannabinoids and Terpenes (R01 Clinical Trial Optional)
  • RFA-OD-19-001, Botanical Dietary Supplements Research Centers (BDSRC) (U19 Clinical Trial Optional).

Improved Methodologies

Many of the research techniques for studying natural products, especially complex mixtures, have remained unchanged over the years and have not yet leveraged advances in biological and chemical methodologies. NCCIH has an interest in catalyzing advances in methods in this area. Examples of recent announcements include:

  • NOT-AT-19-025, Notice of Special Interest for Small Business Research for Methods Development in Natural Products Chemistry
  • RFA-AT-19-003, Center for Natural Product Technology, Methodology, and Productivity Optimization (NP-TEMPO) (U41 Clinical Trial Not Allowed)
  • RFA-AT-19-002, Natural Products NMR Open Data Exchange (NP-NODE) (U24 Clinical Trial Not Allowed).

Natural Product–Drug Interactions

  • NCCIH published two RFAs in 2019 that focused on research into the identity and mechanisms of action of natural products that can interfere with pharmacokinetics of commonly consumed medications.
  • The NIH/NCCIH Natural Product–Drug Interaction (NaPDI) Center of Excellence is addressing issues in the field of (1) consistency in design, implementation, and documentation of studies to assess clinical relevance of natural product–drug interactions and (2) documentation of studies to assess clinical relevance of those interactions.

Other Information

Potential applicants may also be interested in:

3. NCCIH Funding Opportunities

Current Announcements

NCCIH issues specific funding opportunity announcements (FOAs) for narrow areas of high priority. However, we will accept natural product applications through a number of investigator-initiated grant mechanisms. These include the Parent R01 and R21 announcements, the Omnibus SBIR (R43/R44) and STTR (R41/R42) announcements, and the various training mechanisms including fellowships (F), mentored training (K), and institutional training (T).

Past NCCIH Research

Examples of recent NCCIH FOAs for the study of natural products include:

  • RFA-AT-18-003, Discovery and Biological Signatures of Diet-Derived Microbial Metabolites (R01 Clinical Trial Optional)
  • RFA-AT-19-008, Exploring the Mechanisms Underlying Analgesic Properties of Minor Cannabinoids and Terpenes (R01 Clinical Trial Optional)
  • Announcements under the The NIH Centers for Advancing Research on Botanicals and Other Natural Products (CARBON) Program, cofunded with the NIH Office of Dietary Supplements—e.g., RFA-OD-19-001, Botanical Dietary Supplement Research Centers (U19 Clinical Trial Optional)
  • RFA-AT-19-003, Center for Natural Product Technology, Methodology, and Productivity Optimization (U41 Clinical Trial Not Allowed)
  • RFA-AT-19-002, Natural Products NMR Open Data Exchange (U24)
  • RFA-AT-20-002, Center of Excellence for Natural Product Drug Interaction Research (U54 Clinical Trial Required)
  • RFA-AT-20-001, Preclinical Screening for Natural Product Drug Interactions (Clinical Trial Not Allowed, R21).

Research Spotlights—Review selected summaries of published NCCIH research.

Search for NCCIH-funded projects in NIH RePORTER.

NCCIH Contact Information

We encourage you to discuss your proposed research with an NCCIH staff member prior to submitting a grant application. Each program staff member is responsible for coordinating research portfolios in various scientific areas. For specific questions in those areas, please review the list of NCCIH program directors and contact the most appropriate individual.

For general questions about natural product research funding, please contact:

D. Craig Hopp, Ph.D.
Deputy Director, Division of Extramural Research
National Center for Complementary and Integrative Health
National Institutes of Health
hoppdc@mail.nih.gov