NIH/NCCIH – Exploring the Mechanisms Underlying Analgesic Properties of Minor Cannabinoids and Terpenes (R01, R21 Clinical Trial Optional)

The following description was taken from the R01 version of this FOA.

The management of pain has often 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 for the treatment of acute and chronic pain, therefore, 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. To address this question, more research is needed into the basic biological activity 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.  This initiative will not support research on Δ9-tetrahydrocannabinol (THC), this cannabinoid is one of the most abundant and studied of all the cannabinoids. THC has demonstrated analgesic properties; however, its adverse psychoactive effects and abuse potential may increase its risks, limiting its effectiveness as an analgesic. 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, β-caryophyllene, Limonene, α-terpineol, Linalool, α-phellandrene, α-pinene, β-pinene, γ-terpinene, and α-humulene) may have 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 conclusive evidence to support this hypothesis is lacking. It is also unknown how minor cannabinoids and terpenes, either alone or in combination, 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.

Topics of interest include, but are not limited, to the following:

  • To investigate the potential analgesic properties and adverse effects of minor cannabinoids, alone or in combination with each other or terpenes;
  • To investigate the mechanisms by which minor cannabinoids and terpenes may affect pain pathways, including ascending and/or descending neural pathways, cellular and molecular signaling pathways, neuroimmune interactions, or other innovative regulatory pathways related to pain;
  • To explore the impact of sex, age and ethnicity on potential analgesic properties of minor cannabinoids and terpenes;
  • To explore analgesic potential of minor cannabinoids and terpenes for different pain types (e.g., acute pain, chronic pain, inflammatory pain, neuropathic pain);
  • To investigate the pharmacology (pharmacokinetic and pharmacodynamic profiles) of minor cannabinoids and terpenes;
  • To explore binding affinities of minor cannabinoids and terpenes to cannabinoid and opioid and other pain-related receptors;
  • To investigate the impact of dose and/or route of administration on potential analgesic effects of minor cannabinoids and terpenes;
  • To characterize if/how specific terpenes may influence potential analgesic properties of cannabinoids;
  • To explore potential opioid sparing effects of minor cannabinoids and terpenes;
  • To explore the interaction between the microbiome and minor cannabinoids or terpenes;
  • To improve methods to quantify systemic levels of minor cannabinoids and terpenes

This funding opportunity announcement (FOA) supports research in appropriate model organisms or human subjects. As investigators prepare to develop an application, they must determine whether the compounds being used are on the scheduled substance list of the 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. For any application 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 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. 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.

In addition, this FOA supports basic science or mechanistic studies in humans (as appropriate). Human mechanistic studies can be a type of “clinical trial”. NIH defines a mechanistic study as one that is “designed to understand a biological or behavioral process, the pathophysiology of a disease, or the mechanism of action of an intervention” and defines a clinical trial as “a research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes” (NOT-OD-15-015). NCCIH recognizes a difference between clinical trials that are designed to assess efficacy or effectiveness and mechanistic studies that have the primary goal of understanding how an intervention works. This FOA does not allow applications that have any specific aims that propose a clinical trial to assess efficacy or effectiveness of any intervention, such as the impact of cannabinoids or terpenes on changes in pain outcomes such as pain severity, pain interference, or functional outcomes as primary outcomes (this data can be collected as secondary outcomes). However, studies that meet the NIH definition of a clinical trial are acceptable under this FOA provided that their primary outcome/endpoint is explicitly mechanistic. An application that proposes any specific aims that include to measure efficacy/effectiveness as primary outcomes will be considered non-responsive and administratively withdrawn.

Types of Clinical Trials Not Responsive to this FOA

The following types of clinical trials are not responsive to this FOA and applications proposing such activities will be deemed non-responsive and will not be reviewed:

  • Studies 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
  • Multi-site, phase III trials of efficacy (such studies should use the Natural Product UG3/UH3 FOA, PAR-18-696)
  • Single or multi-site observational studies
  • Trials that propose to test natural products for the treatment or prevention of cancer. (Investigators interested in cancer treatment or prevention trials should instead contact the National Cancer Institute).

Deadline:  March 15, 2019 (letters of intent due 30 days prior to deadline)

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