Key Dates

Related Announcements

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

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

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

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-21-160 - NIDCR Clinical Trial Planning and Implementation Cooperative Agreement (UG3/UH3 Clinical Trial Required)

PAR-21-317 - NIDCR Behavioral and Social Intervention Clinical Trial Planning and Implementation Cooperative Agreement (UG3/UH3 Clinical Trial Required

Issued by

National Center for Complementary and Integrative Health (NCCIH)

National Eye Institute (NEI)

National Institute on Aging (NIA)

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

National Institute of Dental and Craniofacial Research (NIDCR)

National Institute on Drug Abuse (NIDA)

National Institute of Neurological Disorders and Stroke (NINDS)

National Cancer Institute (NCI)

All applications to this funding opportunity announcement should fall within the mission of the Institutes/Centers. The following NIH Offices may co-fund applications assigned to those Institutes/Centers.

Office of Dietary Supplements (ODS)

Office of Research on Women's Health (ORWH)

Purpose

This Notice of Special Interest (NOSI) is being issued by the National Center for Complementary and Integrative Health (NCCIH) with participation from multiple NIH Institutes, Centers, and Offices (ICOs). This NOSI aims to promote mechanistic research of therapeutic benefits of minor cannabinoids and terpenes in the cannabis plant. Minor cannabinoids are defined as any and all cannabinoids from the cannabis plant other than Δ9-tetrahydrocannabinol (Δ9-THC). Cannabinoids of particular interest include the following: Δ8-THC, Cannabidiol (CBD), Cannabigerol (CBG), Cannabinol (CBN), Cannabichromene (CBC), cannabichromevarin (CBDV), tetrahydrocannabivarin (THCV), Tetrahydrocannabivarin acid (THCVA), tetrahydrocannabinolic acid (THCA), carmagerol, cannabicitran, sesquicannabigerol. Terpenes of particular interest include the following: Myrcene, ß-caryophyllene, Limonene, α -terpineol, Linalool, α-phellandrene, α-pinene, ß-pinene, β-terpinene, and α-humulene. This NOSI intends to support highly innovative basic and/or mechanistic studies in appropriate model organisms and/or human subjects aiming to investigate the impact of minor cannabinoids and terpenes on mechanisms underlying their therapeutic effects. Preclinical studies of combinations of minor cannabinoids with terpenes or other natural products that may enhance their therapeutic benefits and/or abate unwanted effects are encouraged.

The mechanisms and processes underlying potential contribution of minor cannabinoids and terpenes to symptoms relief and functional restoration may be very broad encompassing different pathological conditions and diseases. This NOSI encourages interdisciplinary collaborations among experts from multiple fields, such as pharmacologists, chemists, physicists, physiologists, neuroscientists, psychologists, endocrinologists, immunologists, geneticists, behavioral scientists, clinicians, or others in relevant areas of inquiry.

Background

A growing body of evidence suggests that cannabis plants may have potential in the treatment of pain, nausea, HIV/AIDS, multiple sclerosis, glaucoma, cancer, epilepsy, obesity, wasting disease, substance use disorders, autoimmune disorders, and other conditions; however, the evidence is largely inconclusive, and further investigation is needed. To dissect potential therapeutic benefits of cannabis from its psychoactive properties, more research is needed into the basic biological activity of the plant’s diverse phytochemicals, specifically minor cannabinoids and terpenes. Cannabis contains more than 110 different cannabinoids and 120 different terpenes. Very few of these phytochemicals have been extensively studied. Δ9-tetrahydrocannabinol (Δ9-THC) is one of the most abundant and studied of all the cannabinoids and it has demonstrated anti-inflammatory and analgesic properties. However, its adverse psychoactive effects and abuse potential may limit its use and effectiveness as an analgesic. This Notice of Special Interest (NOSI) does not support research soley focused on Δ9-THC unless it is used as a control or for comparisons to other minor cannabinoids or terpenes, or to study possible synergistic or additive effects in combination with minor cannabinoids and/or terpenes. Other cannabinoids (e.g., cannabidiol (CBD), Cannabigerol (CBG), and Cannabichromene (CBC)) have been shown to have promising therapeutic benefits and are not thought to be psychoactive or addictive; however, these cannabinoids are less potent than Δ9-THC. Research is needed to further characterize the mechanisms underlying therapeutic potential and other biological properties including adverse effects of these minor cannabinoids as well as the effects of less studied compounds such as Δ8-THC, cannabichromevarin (CBDV), tetrahydrocannabivarin (THCV), Tetrahydrocannabivarin acid (THCVA), tetrahydrocannabinolic acid (THCA), carmagerol, cannabicitran, sesquicannabigerol).

Terpenes comprise a smaller percentage of the phytochemicals in cannabis but give the plant its strain-specific properties such as aroma and taste. Terpenes can be found in other plants (e.g., fruits, vegetables and edible herbs). Unlike cannabinoids, terpenes are not controlled substances. There is evidence to suggest that specific terpenes (e.g., Myrcene, ß-caryophyllene, Limonene, α-terpineol, Linalool, α-phellandrene, α-pinene, ß-pinene, γ-terpenes, and α-humulene) may have therapeutic benefits, for example, analgesic or anti-inflammatory properties; however, more research is needed to bolster the evidence base and understand their underlying mechanisms of action. One of the putative mechanisms of action is that terpenes can influence the activity of cannabinoids or signaling from the cannabinoid receptors, but evidence to support this hypothesis is limited. It is also unknown how minor cannabinoids and terpenes, either alone or in combination, may modulate the biological and neural systems associated with certain pathologic condition.

To shed a light on the current and future landscapes for cannabis research within the present regulatory environment, NCCIH sponsored a workshop in December 2018 on “Evaluating the Therapeutic Potential of Cannabinoids: How to Conduct Research Within the Current Regulatory Framework” where the research foci and portfolios of the four NIH Institutes and Centers involved in cannabinoid and cannabis research were described. NCCIH prioritized research on terpenes and minor cannabinoids as it relates to pain and comorbid conditions (anxiety, depression), nociception, and inflammation. Since the workshop, NCCIH published two funding opportunities, RFA-AT-19-008 and RFA-AT-19-009 supporting innovative basic and mechanistic research studies focusing on uncovering the potential pain-relieving properties of minor cannabinoids and terpenes and underlying mechanisms of their impact on pain. In addition, in December 2019, NCCIH issued a NOSI NOT-AT-20-002 on Exploring the Mechanisms Underlying Analgesic Properties of Minor Cannabinoids and Terpenes.

With increased interests in cannabinoid and cannabis research beyond its analgesic effects, this NOSI aims to broaden the focus on therapeutic benefits of minor cannabinoids and terpenes from pain to other symptoms, conditions and diseases that are of interests to other NIH ICOs. Furthermore, other biological properties of these compounds including adverse effects can be evaluated as long as the primary focus of the proposed research will be on their therapeutic benefits.

Research Objectives and Participating ICO Interests

The scope of research to be supported through this NOSI is broad and encourages research on therapeutic properties of minor cannabinoids and terpenes in appropriate model organisms or mechanistic trials with research volunteers.

Applicants are strongly encouraged to consult the Scientific/Research Contact listed below to discuss the alignment of their proposed work with the goals of this funding opportunity announcement (FOA) and the participating ICO interests.

National Center for Complementary and Integrative Health (NCCIH)

NCCIH is interested in supporting research grant applications to study minor cannabinoids and terpenes in the cannabis plant as it relates to pain and/or nociception. Topics of high program priorities include: 1) studies on the mechanisms by which minor cannabinoids and terpenes may affect pain pathways, including cellular and molecular signaling pathways, neuroimmune interactions, or other innovative regulatory pathways related to pain; 2) studies on the interaction between the microbiome and minor cannabinoids or terpenes; 3) studies on how specific terpenes may influence potential analgesic mechanisms of understudied minor cannabinoids; 4) studies on multimodal approaches to analgesia that include minor cannabinoids and terpenes.

Applications proposing a clinical trial must follow the Consolidated Notice on NCCIH Clinical Trials Policies at NOT-AT-20-001 as only mechanistic clinical trials will be accepted by NCCIH through this NOSI. As investigators prepare to develop an application, they must determine whether the compounds being used are on the scheduled substance list of the U.S. Drug Enforcement Agency (DEA). If so, then they should determine whether there is a need to obtain investigator registration and site licensure to conduct the proposed research. All applications must indicate whether DEA registration and licensure are needed, and whether these items are in place.

For any application that includes delivering cannabinoids or terpenes 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. If the FDA determines that the proposed research needs to be conducted under an IND, the IND must be submitted before an award is made and all “Clinical Hold” issues need to be resolved for the proposed human research before an award is made. In the application, the investigator should describe the timeline for obtaining the IND or provide the IND number, if the investigator already holds one.

Other ICOs

Applications not in line with the priority topics described under the ICO interests will be considered as non-responsive to this NOSI.

National Cancer Institute (NCI)

NCI is interested in promoting research to understand the mechanisms by which minor cannabinoids and terpenes in the cannabis plant may affect cancer interception, cancer treatment and resistance, and management of cancer symptoms. Topics of particular interest to NCI include 1) examining how minor cannabinoids and terpenes influence immune function and inflammatory pathways during cancer therapy; 2) identifying how these minor constituents, either alone or in combination, modulate cancer signaling pathways and influence therapeutic outcomes in cancer; 3) characterizing potential adverse effects of minor cannabinoids and terpenes while studying the mechanism of action for these compounds in cancer treatment; and 4) defining mechanisms of action for minor cannabinoids and terpenes in the management of cancer symptoms. Applicants interested in mechanisms by which cannabis and cannabinoids affect cancer biology, cancer interception, cancer treatment and resistance, and management of cancer 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

National Eye Institute (NEI)

The NEI is interested in exploring the therapeutic benefits of terpenes and minor cannabinoids in the treatment of glaucoma, retinal degenerations and uveitis. Mechanistic studies to elucidate the role of these compounds as well as endocannabinoids in pathways that are fundamental to understanding the pathophysiology of these diseases are encouraged.

National Institute on Aging (NIA)

The National Institute on Aging is interested in supporting research grant applications to study minor cannabinoids and terpenes in the cannabis plant in the context of aging. Applications may focus on, but are not limited to: understanding mechanisms of minor cannabinoids and terpenes in the setting of pain and/or nociception, age-related cognitive decline/impairment, Alzheimer’s disease and Alzheimer’s disease-related dementias (AD/ADRD), weight loss/cachexia, sleep, or conditions in palliative care settings; and aging-related changes in the endocannabinoid system and other physiologic systems (e.g., renal, musculoskeletal, central nervous system) affecting cannabinoid metabolism and mechanisms of action, and in relation to multiple chronic conditions and polypharmacy.

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

NIAAA is interested in research exploring the role of endocannabinoid systems in alcohol misuse and alcohol use disorder (AUD), medication development for alcohol misuse and AUD targeting endocannabinoid pathways;, CBD and other minor cannabinoids and terpenes for the treatment of AUD, brain mechanisms shared by alcohol use disorder and other substance (including cannabis) use disorders.

National Institute on Drug Abuse (NIDA)

NIDA supports mechanistic research on therapeutic and other biological properties of minor cannabinoids in the context of substance use and/or substance use disorder (SUD), and comorbidity of SUD and HIV infection. Basic and human research are encouraged to study the relationships between alteration of endocannabinoid systems and other endogenous modulators of nervous and immune systems. These studies should inform molecular targets or ligand development for function improvement and symptom management. This NOSI also encourages the use of multiple biological models (cell/tissue, biological specimens or postmortem brain tissue from treated or untreated SUD patients, animal models) to establish biological relevance and translational validity of findings.

National Institute of Dental and Craniofacial Research (NIDCR)

The endocannabinoid system may be a target for the treatment of oral, dental and craniofacial diseases, as suggested by the distribution of transient receptor potential (TRP) channels and/or cannabinoid (CB) receptors in the human oral mucosa, salivary glands, periodontal ligament, synovial tissue of the temporomandibular joint, as wells as central nervous system and immune system cells. NIDCR is interested in mechanistic, pre-clinical or clinical studies on the analgesic, immune-mediating, anti-inflammatory, apoptotic, or other potential therapeutic properties of minor cannabinoids and terpenes for dental, oral or craniofacial diseases or conditions. NIDCR is also interested in studies of the interaction between the oral microbiome and minor cannabinoids or terpenes. Human subjects interventions with Delta-9-tetrahydrocannabinol (Δ9-THC) will be considered non-responsive. For any application that includes delivering cannabinoids or terpenes 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. Clinical trials submitted through a Parent R01 or R21 will not be accepted.

NIDCR will only accept applications submitted through these FOAs or their subsequent reissued equivalents.

National Institute of Neurological Disorders and Stroke (NINDS)

• NINDS will accept R01 research grant applications, in its mission, to study minor cannabinoids and terpenes from the cannabis plant as it relates to neurological disorders, including but not restricted to pain, migraine, headache, epilepsy, movement disorders, neurodegenerative disorders, and stroke.

• NINDS will not accept R21 proposals in response to this NOSI.

• NINDS will not accept applications proposing a clinical trials or research that includes delivering cannabinoids or terpenes to humans in response to this NOSI.

NINDS will only accept applications submitted through these FOAs or their subsequent reissued equivalents.

Office of Research on Women's Health (ORWH)

The Office of Research on Women’s Health (ORWH) is within the Office of the Director of NIH and works in partnership with the 27 NIH Institutes and Centers to ensure that women's health research is part of the scientific framework of the NIH and the larger scientific community. The cannabis plant and cannabis derivatives may have potential use in the treatment of pain, glaucoma, cancer, autoimmune disorders such as multiple sclerosis, obesity, as well as other diseases and conditions that may have a different onset, course, and outcome in women. There is a critical need to include women in mechanistic research studies on minor cannabinoids and terpenes to understand the mechanisms underlying their therapeutic effects. Integrating the purposeful accounting for sex as a biological variable (SABV) in biomedical research on cannabinoid use and understanding the effects of cannabinoids (both beneficial and adverse) throughout the life span will fill gaps in our knowledge and inform more effective, personalized approaches to speed the transition to more effective individualized medicine. For additional guidance, review the 2019-2023 Trans-NIH Strategic Plan for Women’s Health Research.

Application and Submission Information

This Notice applies to applications with due dates on or after October 5, 2022, and subsequent receipt dates through June 5, 2024.Submit applications for this Notice using one of the below Funding Opportunity Announcements (FOAs) or any reissues of these announcements through the expiration date of this notice. All instructions for the Parent Announcements must be followed.

Applicants must select the IC and associated FOA to use for submission of an application in response to the NOSI. The selection must align with the IC requirements listed in order to be considered responsive to that FOA. Non-responsive applications will be withdrawn from consideration for this initiative. In addition, applicants using NIH Parent announcements (listed below) will be assigned to those ICs on this NOSI that have indicated those FOAs are acceptable and based on usual application-IC assignment practices.

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

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

Submit applications for this initiative using one of the below FOAs:

• For funding consideration, applicants must include "NOT-AT-22-027" (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.

Although NCCIH is not listed as a Participating Organization in all the FOAs listed above, applications for this initiative will be accepted.

Applications nonresponsive to terms of this NOSI will be withdrawn from consideration for this initiative.

Inquiries