Key Dates

Related Announcements

PA-20-185- NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)

PA-20-184- Research Project Grant (Parent R01 Basic Experimental Studies with Humans Required)

PA-20-183- Research Project Grant (Parent R01 Clinical Trial Required)

PA-20-194- NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Required)

PA-20-195- NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed)

PA-20-196- NIH Exploratory/Developmental Research Grant Program (Parent R21 Basic Experimental Studies with Humans Required)

PAR-20-224- Avenir Award Program for Research on Substance Use Disorders and HIV/AIDS (DP2 Clinical Trial Optional)

PAR-20-221- NIDA Avant-Garde Award Program for HIV/AIDS and Substance Use Disorder Research (DP1, Clinical Trial Optional)

PA-20-187- NIH Pathway to Independence Award (Parent K99/R00 Independent Clinical Trial Required)

PA-20-188- NIH Pathway to Independence Award (Parent K99/R00 Independent Clinical Trial Not Allowed)

PA-20-189- NIH Pathway to Independence Award (Parent K99/R00 Independent Basic Experimental Studies with Humans Required)

PA-20-190- Mentored Research Scientist Development Award (Parent K01 - Independent Clinical Trial Not Allowed)

PA-20-191- Mentored Research Scientist Development Award (Parent K01 Independent Basic Experimental Studies with Humans Required)

PA-20-176- Mentored Research Scientist Development Award (Parent K01 - Independent Clinical Trial Required)

PA-20-208- Substance Use/Substance Use Disorder Dissertation Research Award (R36 - Clinical Trials Optional)

PAR-22-201- NIDA Program Project Grant Applications (P01 Clinical Trial Optional)

PAR-22-060- Research Enhancement Award Program (REAP) for Health Professional Schools and Graduate Schools (R15 Clinical Trial Not Allowed)

PA-20-186- Midcareer Investigator Award in Patient-Oriented Research (Parent K24 Independent Clinical Trial Not Allowed)

PA-20-192- Midcareer Investigator Award in Patient-Oriented Research (Parent K24 Independent Basic Experimental Studies with Humans Required)

PAR-21-035 Cancer Prevention and Control Clinical Trials Grant Program

PAR-22-216- NCI Clinical and Translational Exploratory/Developmental Studies

Issued by

National Institute on Drug Abuse (NIDA)

National Institute of Dental and Craniofacial Research (NIDCR)

National Cancer Institute (NCI)

Purpose

This Notice of Special Interest (NOSI) encourages studies of the endocannabinoid system (ECS) and its roles in brain health and acute and chronic disease, substance use, and substance use disorder (SUD). The desired outcomes of research will be a mechanistic understanding of how cannabinoids and manipulation of the ECS can elicit both therapeutic and deleterious effects as well as the role of cannabinoids and ECS in symptom management.

Background

The ECS, which is expressed throughout the vertebrate central nervous system and periphery, is composed of three key components: 1) the endocannabinoids, 2) their synthetic and metabolic enzymes, and 3) the cannabinoid receptors. In addition to the known endocannabinoids, there have been additional endogenous ligands discovered, but their functions at the receptors are largely unknown. Endocannabinoids and cannabinoids exert their actions by binding to membrane bound cannabinoid receptors, classified as type 1 and type 2 (CB1 and CB2). Endocannabinoids are produced and released on demand and act via their major receptors to impact a diverse array of cellular signal transduction pathways. As a retrograde signaling system that sends activity-modifying signals back to the initiating cells, there is a particular state-dependent aspect of the ECS that enables it to act as a broad-spectrum modulator of physiological processes. Numerous studies have shown analgesic and anti-inflammatory effects resulting from activation of CB1 and CB2, which have implicated the ECS in the body’s ability to adapt in response to perturbations. Although engaging the ECS may be adaptive and promote physiological resilience and restoration, dysregulation of the ECS by exogenous cannabinoid use may have deleterious consequences. Elucidating the roles of the ECS in disease states and sequelae as well as normative functions, and the consequences of cannabis use on the ECS will inform public health.

Research Objectives

Studies conducted in various biological model systems have implicated engagement of ECS in central nervous system development, neural synaptic organization, and plasticity, and in cellular responses to injury or disease. These studies have been used as a basis for supporting the therapeutic uses of cannabis. However, conflicting clinical reports suggest both positive and negative effects of cannabinoids. As a widespread modulator system that impacts the functions of various tissues and organs, alterations in the ECS (either hypo- or hyper- activation) may disrupt molecular networks that are critical for physiological stabilization. Given these conflicting views, this NOSI encourages research to explore and validate roles of the ECS under physio-normative and disease conditions, including their sequelae, and the impacts of recreational or medicinal cannabinoid use (acute and/or chronic).

The research supported by this NOSI includes, but is not limited to: 1) research to identify the causal mechanisms underlying therapeutic benefits of cannabinoids and the ECS; 2) studies utilizing pharmacological, immunological, or genetic approaches to manipulate specific elements of the ECS; 3) research to establish biological relevance and translational validity of findings using biological models (cell/tissue, biological specimens, or postmortem brain tissue from treated or untreated SUD patients); and 4) research to investigate the role of cannabinoids and the ECS in treatment-related conditions. This NOSI also encourages research examining the longitudinal effects of cannabinoid use in order to describe biological mechanisms associated with persistent ECS dysregulation. Key in this regard is the collection of data on parameters such as dose, frequency and duration of exposure.

National Institute on Drug Abuse (NIDA)

NIDA supports mechanistic research on the biological effects of cannabinoids, both endogenous and exogenous in nature. The roles of the ECS in drug use, the therapeutic potential of ECS modulation in the context of substance use and/or SUD, as well as comorbidity of SUD and HIV infection are of particular interest. Although engaging the ECS may be adaptive and promote physiological resilience and restoration, basic and human research are encouraged to study the relationships between alteration of ECS functions and modulation of nervous and immune systems. These studies should inform molecular targets and/or ligand development for functional recovery and symptom management.

National Institute of Dental and Craniofacial Research (NIDCR)

NIDCR supports rigorously designed basic science, translational and clinical research studies, including longitudinal studies, investigating the causal mechanisms that link ECS changes to the onset, progression, management or resolution of dental, oral and craniofacial diseases. Research studies may investigate ECS-modulated behavioral and systemic changes that can directly and substantially impact the prevention, diagnosis or prognosis of dental, oral or craniofacial diseases (primary outcomes). For any application that includes delivering ECS-related products to humans, investigators must contact the U.S. Food and Drug Administration (FDA) prior to applying regarding whether an Investigational New Drug (IND) application is necessary for the proposed clinical research. NIDCR does not accept clinical trials submitted through a Parent R01 or R21. When applying, investigators should reference this NOSI and select an activity among those listed in this NOSI that includes NIDCR among the participating ICs.

National Cancer Institute (NCI)

NCIs mission is to lead, conduct, and support cancer research across the nation to advance scientific knowledge and help all people live longer, healthier lives. NCI is interested in supporting clinical trial research to investigate the impact of cannabinoids and the ECS in cancer treatment-related symptoms, such as pain, fatigue, insomnia, nausea and vomiting, diarrhea, mucositis, and poor appetite. Applicants interested in submitting cancer clinical trial research should use one of the following Funding Opportunity Announcements: for R01 submissions use PAR-21-03, “Cancer Prevention and Control Clinical Trials Grant Program” and for R21 submissions PAR-22-216, “NCI Clinical and Translational Exploratory/Developmental Studies.” Applicants interested in preclinical research on the role of cannabinoids and the ECS in cancer treatment-related symptoms should apply directly to NCI NOSI entitled “Notice of Special Interest (NOSI): Basic Mechanisms of Cannabis and Cannabinoid Action in Cancer,” NOT-CA-22-085 rather than to this trans-NIH NOSI.

Other application considerations:

1. Applicants MUST consult with NIH IC Scientific/Research Contacts when developing plans for an application. Early contact will provide an opportunity to clarify priorities to the specific NIH institute, an important message in the cover letter to inform NIH Center of Scientific Review about a desirable specific IC assignment and the NIH definition regarding Basic Experimental Studies with Humans (BESH).
2. The selection of molecular targets, variables and functional outcomes must be justified.
3. Studies should address inter-relationships among downstream signaling processes. For example, studies of ECS effects on inflammation should examine both pro- and anti-inflammatory markers.
4. Applications proposing research on cannabis or its main psychotropic constituent delta-9-THC are required to measure and report results using a standard delta-9-THC unit in all applicable human subjects research. The goal is to increase the comparability across cannabis research studies. A standard delta-9-THC unit is defined as any formulation of cannabis plant material or extract that contains 5 milligrams of delta-9-THC. A justification should be provided for human research that does not propose to use the standard unit. Please see NOT-DA-21-049 for additional details.
5. For human studies, stratification of research subjects should be justified.

Application and Submission Information

This notice applies to due dates on or after February 5, 2023 and subsequent receipt dates through January 8, 2026

Submit applications for this initiative using one of the following funding opportunity announcements (FOAs) or any reissues of these announcement through the expiration date of this notice.

• PA-20-185- NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)
• PA-20-184- Research Project Grant (Parent R01 Basic Experimental Studies with Humans Required)
• PA-20-183- Research Project Grant (Parent R01 Clinical Trial Required)
• PA-20-194- NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Required)
• PA-20-195- NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed)
• PA-20-196- NIH Exploratory/Developmental Research Grant Program (Parent R21 Basic Experimental Studies with Humans Required)
• PAR-20-224- Avenir Award Program for Research on Substance Use Disorders and HIV/AIDS (DP2 Clinical Trial Optional)
• PAR-20-221- NIDA Avant-Garde Award Program for HIV/AIDS and Substance Use Disorder Research (DP1, Clinical Trial Optional)
• PA-20-187- NIH Pathway to Independence Award (Parent K99/R00 Independent Clinical Trial Required)
• PA-20-188- NIH Pathway to Independence Award (Parent K99/R00 Independent Clinical Trial Not Allowed)
• PA-20-189- NIH Pathway to Independence Award (Parent K99/R00 Independent Basic Experimental Studies with Humans Required)
• PA-20-190- Mentored Research Scientist Development Award (Parent K01 - Independent Clinical Trial Not Allowed)
• PA-20-191- Mentored Research Scientist Development Award (Parent K01 Independent Basic Experimental Studies with Humans Required)
• PA-20-176- Mentored Research Scientist Development Award (Parent K01 - Independent Clinical Trial Required)
• PA-20-208- Substance Use/Substance Use Disorder Dissertation Research Award (R36 - Clinical Trials Optional)

• PAR-22-201- NIDA Program Project Grant Applications (P01 Clinical Trial Optional)

• PAR-22-060- Research Enhancement Award Program (REAP) for Health Professional Schools and Graduate Schools (R15 Clinical Trial Not Allowed)

• PA-20-186- Midcareer Investigator Award in Patient-Oriented Research (Parent K24 Independent Clinical Trial Not Allowed)
• PA-20-192- Midcareer Investigator Award in Patient-Oriented Research (Parent K24 Independent Basic Experimental Studies with Humans Required)

• PAR-21-035 Cancer Prevention and Control Clinical Trials Grant Program

• PAR-22-216- NCI Clinical and Translational Exploratory/Developmental Studies

All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:

• For funding consideration, applicants must include “NOT-DA-22-048" (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

• Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.

Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.

Inquiries

Scientific/Research Contact(s)

Yu (Woody) Lin, PhD
National Institute on Drug Abuse (NIDA)
Telephone: 301-435-1318
Email: ylin1@mail.nih.gov

Lorena Baccaglini, DDS, MS, PhD (clinical research)
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-435-7908
Email: lorena.baccaglini@nih.gov

Melissa M Ghim, PhD (basic science research)
National Institute of Dental & Craniofacial Research (NIDCR)
Phone: (301) 529-6570
E-mail: melissa.ghim@mail.nih.gov

Sharon Ross, PhD
National Cancer Institute (NCI)
Telephone: 240-276-7124
Email: rosssha@mail.nih.gov

Alexis Bakos, PhD
National Cancer Institute (NCI)
Telephone: 301-921-5970
Email: alexis.bakos@nih.gov

Financial/Grants Management Contact(s)

Juliette Lee
National Institute on Drug Abuse (NIDA)
Telephone: 301-402-7744
Email: juliette.lee@nih.gov

Amy R. Bartosch
National Cancer Institute (NCI)
Telephone: 240-276-6375
Email: amy.bartosch@nih.gov