Notice of Intent to Publish a Funding Opportunity Announcement for Exploring the Mechanisms Underlying Analgesic Properties of Minor Cannabinoids and Terpenes (R01, Clinical Trial Optional)

Notice Number: NOT-AT-19-008

Key Dates

Release Date: November 07, 2018
Estimated Publication Date of Funding Opportunity Announcement: January 08, 2019
First Estimated Application Due Date: March 08, 2019
Earliest Estimated Award Date: September 10, 2019
Earliest Estimated Start Date: September 10, 2019

Related Announcements

Issued by
National Center for Complementary and Integrative Health (NCCIH)


The National Center for Complementary and Integrative Health (NCCIH) intends to publish a Funding Opportunity Announcement (FOA) to solicit applications for research on minor cannabinoids and terpenes in the cannabis plant as it relates to pain and nociception. Minor cannabinoids are defined as all and any cannabinoids from the cannabis herb other than ?9-tetrahydrocannabinol (?9-THC). Cannabinoids and terpenes of particular interest include: Cannabidiol (CBD), Cannabigerol (CBG), Cannabinol (CBN), Cannabichromene (CBC), Myrcene, -caryophyllene, Limonene, a-terpineol, Linalool, a-phellandrene, a-pinene, -pinene, ?-terpinene, and a-humulene. This initiative intends to support highly innovative basic and/or mechanistic studies in appropriate model organisms and/or human subjects aiming to identify, describe and predict if minor cannabinoids and/or terpenes can help treat pain. The mechanisms and processes underlying potential contribution of minor cannabinoids and terpenes to pain relief and functional restoration in patients with different pain conditions may be very broad. This initiative encourages interdisciplinary collaborations by experts from multiple fields pharmacologists, chemists, physicists, physiologists, neuroscientists, psychologists, endocrinologists, immunologists, geneticists, behavioral scientists, clinicians, and others in relevant fields of inquiry.

This Notice is being provided to allow potential applicants sufficient time to develop meaningful collaborations and responsive projects, as well as to give potential applicants sufficient time to determine whether they need to obtain investigator registration and site licensure from the Drug Enforcement Agency (DEA) ,if appropriate. For applications that include human use of any of the compounds, this Notice provides time to determine whether an Investigational New Drug (IND) application is needed, or if the FDA will provide a written waiver indicating that an IND is not needed for the proposed research. No awards will be made to the investigators in the absence of appropriate FDA/IND documentations for proposed human subject studies.

The FOA is expected to be published in Winter 2019 with an expected application due date in March 2019.

The FOA will utilize the R01 activity code. Details of the planned FOA are provided below.

Research Initiative Details

Chronic pain impacts over one third of the U.S. population, consumes substantial health care resources, and significantly reduces work productivity. Long-term management of chronic pain has largely relied on opioid-based pharmacologic interventions, which not only lack long-term efficacy but also carry risks for adverse events and contribute to the national epidemic of opioid misuse. The development or identification of novel pain management strategies is a high priority and unmet need. Natural products have historically been a source of novel analgesic compounds developed into pharmaceuticals (e.g., willow bark to aspirin). A growing body of literature suggests that the cannabis plant may have analgesic properties; however, research into cannabis’s potential analgesic properties has been slow. One key mechanism to investigate is whether potential analgesic properties of cannabis can be separated from its psychoactive properties. In order to address this question, more research is needed into the basic biology of the plant’s diverse phytochemicals, specifically minor cannabinoids and terpenes.

Cannabis contains over 110 different cannabinoids and 120 different terpenes. Very few of these phytochemicals have been extensively studied. While this initiative will not support research on ?9-tetrahydrocannabinol (THC), this cannabinoid is one of the most abundant and studied of all the cannabinoids. THC has demonstrated analgesic properties, however its psychoactive effects on the mind, emotions and behavior limit its desirability for analgesia. Other cannabinoids (e.g., cannabidiol (CBD), Cannabigerol (CBG), and Cannabichromene (CBC)) have been shown to have analgesic or anti-inflammatory properties and are not thought to be psychoactive or addictive; however, these cannabinoids are not as potent as THC. 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), and unlike cannabinoids they are not controlled substances. There is evidence to suggest that specific terpenes (e.g., Myrcene, -caryophyllene, Limonene, a-terpineol, Linalool, a-phellandrene, a-pinene, -pinene, ?-terpinene, and a-humulene) may have analgesic or anti-inflammatory properties; however, more research is needed to understand 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 conclusive evidence to support this hypothesis is lacking. It is also unknown how minor cannabinoids and terpenes, either alone or in conjunction with each other, may modulate the biological and neural systems associated with pain perception and analgesia.

Early clinical data suggest that cannabis may enhance the potency of opioids in relieving pain; and the synergy from using these products together may result in more effective pain relief with lower doses of opioids. Yet, it is unclear which components of cannabis may have these properties. In particular, few studies have examined whether and which cannabinoids and/or terpenes interact with the opioid pain pathways. More specific research is therefore needed to uncover the mechanisms of action for minor cannabinoids and terpenes, as well as whether these molecules, alone or in combinations, can be used to treat pain, opioid use disorder and other pain-related comorbidities.

As investigators prepare to develop an application, they must determine if the compounds being used are on the scheduled substance list of the Drug Enforcement Agency (DEA) to determine if there is a need to obtain investigator registration and site licensure to conduct the proposed research For any proposal that includes delivering cannabinoids or terpenes to humans, investigators must contact the US 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. In the application, the investigator is encouraged to describe the timeline for obtaining the IND or provide the IND number, if the investigator already holds one. If the FDA determines an IND is not necessary for the proposed human research, the investigator will need to provide a copy of a written waiver from the FDA in the application or prior to award.

This FOA will not support clinical trials proposing to examine efficacy such as the impact of cannabinoids or terpenes on changes in pain outcomes such as pain severity, pain interference, or functional outcomes.

Funding Information

Estimated Total Funding NCCIH intends to commit up to $1,500,000 in FY 2019
Expected Number of Awards 4
Estimated Award Ceiling $350,000 per award annually in direct costs.
Primary CFDA Numbers 93.213

Anticipated Eligible Organizations

Public/State Controlled Institution of Higher Education
Private Institution of Higher Education
Nonprofit with 501(c)(3) IRS Status (Other than Institution of Higher Education)
Nonprofit without 501(c)(3) IRS Status (Other than Institution of Higher Education)
Small Business
For-Profit Organization (Other than Small Business)
State Government
Indian/Native American Tribal Government (Federally Recognized)
County governments
City or township governments
Special district governments
Independent school districts
Public housing authorities/Indian housing authorities
Indian/Native American Tribally Designated Organization (Native American tribal organizations (other than Federally recognized tribal governments)
U.S. Territory or Possession
Indian/Native American Tribal Government (Other than Federally Recognized)
Regional Organization

Applications are not being solicited at this time.


Please direct all inquiries to:

Inna Belfer, M.D., Ph.D.
National Center for Complementary and Integrative Health (NCCIH)