The mechanisms and processes underlying potential contribution of minor cannabinoids and terpenes to pain relief and functional restoration may be very broad encompassing different pain conditions. 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.
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 contributing 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 public health priority and unmet need. Natural products have historically been sources 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; more research, however, is needed to explore the potential analgesic properties of cannabis. 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 more than 110 different cannabinoids and 120 different terpenes. Very few of these phytochemicals have been extensively studied. 9-tetrahydrocannabinol (THC) is one of the most abundant and studied of all the cannabinoids and it has demonstrated analgesic properties. However, its adverse psychoactive effects and abuse potential may s may limit its use and effectiveness as an analgesic. This Notice of Special Interest (NOSI) does not support research on THC unless it is used as a control or for comparisons to other minor cannabinoids or terpenes. 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 less potent than 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). Unlike cannabinoids terpenes are not controlled substances. There is evidence to suggest that specific terpenes (e.g., Myrcene, ß-caryophyllene, Limonene, a -terpineol, Linalool, a -phellandrene, a -pinene, ß-pinene, terpenes, and a 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.
Some 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 endogenous opioid pain pathways. More specific research is therefore needed to uncover the mechanisms of action for minor cannabinoids and terpenes in the context of pain, opioid use disorder and other pain-related comorbidities.
This NOSI supports research in appropriate model organisms or mechanistic trials with volunteer participants. 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. Note that no award will be made until all DEA requirements are met. 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. 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.
Areas of interest include, but are not limited to, the following:
- Investigate the potential analgesic mechanisms and adverse mechanistic effects of minor cannabinoids, alone or in combination with each other or terpenes
- 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
- Explore the impact of sex, age and ethnicity on potential analgesic mechanisms of minor cannabinoids and terpenes
- Explore analgesic mechanisms of minor cannabinoids and terpenes for different pain types (e.g., acute pain, chronic pain, inflammatory pain, neuropathic pain)
- Explore binding affinities of minor cannabinoids and terpenes to cannabinoid and opioid and other pain-related receptors
- Investigate the impact of dose and/or route of administration on potential analgesic mechanisms of minor cannabinoids and terpenes
- Characterize if/how specific terpenes may influence potential analgesic mechanisms of cannabinoids
- Explore potential opioid sparing mechanisms of minor cannabinoids and terpenes
- Explore the interaction between the microbiome and minor cannabinoids or terpenes
- Improve methods to quantify systemic levels of minor cannabinoids and terpene
- Topics that are not within the scope of this NOSI include:
The following types of clinical trials will be considered nonresponsive to this NOSI:
- Studies to investigate the pharmacology (pharmacokinetic and pharmacodynamic profiles) of minor cannabinoids and terpenes in humans exclusively (such studies should use the NCCIH Natural Product FOA PAR-18-829)
- Studies to investigate the impact of dose and/or route of administration on potential clinical effects of minor cannabinoids and terpenes in humans (such studies should use the NCCIH Natural Product FOAs: PAR-18-829, PAR-18-828, PAR-18-125, or PAR-18-696)
- 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 NCCIH Natural Product UG3/UH3 FOA, PAR-18-696)
- Single or multi-site observational studies focusing on clinical outcomes in humans
- Trials that propose to test cannabinoids or terpenes for the treatment or prevention of cancer. (Investigators interested in cancer treatment or prevention trials should instead contact the National Cancer Institute)