NIH – Developing the Therapeutic Potential of the Endocannabinoid System for Pain Treatment (R01 – Clinical Trial Optional)

September 21, 2018 by School of Medicine Webmaster

Pain is a substantial public health issue, where it is estimated that about 100 million Americans suffer from chronic pain.  Opioids have been increasingly used to treat chronic pain, and there has been an increase in the number of opioid prescriptions, which has caused a concomitant rise in prescription opioid abuse.  While opioids may be effective in treating chronic pain in some cases, other treatment options are desperately needed.  One such option is to explore and develop medications that work through the cannabinoid system to help reduce pain.

Recently there has been a resurgence in interest in the potential medical utility of cannabis and its constituents.  Certainly, public perception is that cannabis has therapeutic benefit, especially in the treatment of pain, and there is some preliminary epidemiological and clinical research that supports possible benefits, yet to date there have not been adequate large controlled trials to support these claims.  Moreover, the use of an unprocessed plant or crude extract, in which constituents vary and dosing is difficult to control, would not be an optimal design for a medication.  In contrast, cannabis constituents, especially tetrahydrocannabinol (THC) and cannabidiol (CBD), or synthetic cannabinoids (e.g. CB2 agonists), and the endocannabinoid system are promising entities that are currently under investigation as potential targets for pain treatments. Despite some positive outcomes, none of the cannabinoid-based drugs have yet been approved by the FDA for pain treatment. More clinical and mechanism-based basic research is warranted to develop safe and effective cannabinoid-based pain treatments.

Several small trials have demonstrated that cannabis can reduce the sensation of pain, including additive effects over those achieved from concurrent medications.  Research is needed to examine cannabis-related compounds as alternative therapies for pain management. Important in this endeavor is to develop a deeper understanding of the role of natural cannabinoids and endocannabinoids in pain perception, processes, and outcomes.  Research is also needed to determine how to modulate key endocannabinoid receptors, ligands, and enzyme levels in pain conditions.  This funding opportunity announcement (FOA) encourages research project grant (R01) applications that study cannabinoids (phytocannabinoids and synthetic cannabinoids) and the endocannabioid system to evaluate the therapeutic potential of the endocannabinoid system across a variety of pain conditions.


The purpose of this NIH Pain Consortium-endorsed FOA is to support projects examining the therapeutic potential of cannabinoids and endocannabinoid system across a variety of pain conditions. Research supported under this FOA is wide-ranging.  In general, the goal is to understand the role of cannabinoids in the management of chronic pain, in part, to help mitigate the high rate of use and abuse of opioids.

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

  • Understand the role of cannabinoids and endocannabinoids in the transition of acute pain to chronic pain
  • Understand the interactive role of cannabinoids, endocannabinoids, and opioid system in pain signaling
  • Study the spatial and temporal regulation of cannabinoid receptor expression at various stages of pain processes
  • Understand the role of endocannabinoid ligands and ligand-metabolizing enzymes in pain conditions.
  • Determine if the endocannabinoid system genes are regulated differently under pain conditions (role of epigenetics, gene expression, cis-/trans-effects, etc.)
  • Determine the potential for biased agonists, hybrid dual ligands, or allosteric modulators that include cannabinoid receptor targets with other targets (e.g. opioid receptors, TRP channels, etc.) as possible mechanisms for analgesia
  • Study the potential therapeutic efficacy of non-psychotropic phytocannabinoids found in cannabis, such as CBD, Tetrahydrocannabivarin (THCV), or others.
  • Parse the effects of cannabis vs. THC vs CBD and their role in modulating the endocannabinoid system in various pain states
  • Understand interaction between cannabinoids, endocannabinoid system, inflammation, and pain
  • Understand the role of cannabinoids in co-morbid pain conditions (e.g. diabetes, depression, HIV, cancer, etc.)
  • Use of novel approaches such as social media or hospital/clinical-based observational studies on the use of medical marijuana by patients with pain indications.

In addition to the topics listed above, additional specific areas of interest for some of the participating ICs are outlined below.  Applicants are encouraged to contact the participating IC’s Scientific/Research contact to discuss the submission and gauge the interest of the participating institute.

NIDA: Examine the role of various combinations and potencies of the two main cannabinoids (THC and CBD) and their effects on modulating the endocannabinoid system for pain perception and analgesia; effects of long-term endocannabinoid system therapies on addiction liability.

NCI: The role of cannabinoids and the endocannabinoid system in the treatment tumor-related pain conditions, such as metastatic bone pain, and painful conditions arising from the treatment of cancer, such as chemotherapy induced peripheral neuropathy, aromatase inhibitor arthralgias, and radiation induced stomatitis.

NCCIH: The role of naturally occurring phytocannabinoids and their derivatives either alone or in conjunction with other complementary approaches (e.g. other natural products, mind-body programs) in modulating the biological and neural systems associated with pain perception and analgesia in relevant model organisms or human subjects as well as the mechanisms underlying cannabinoid analgesic and anti-inflammatory properties. NCCIH will not fund research proposing efficacy or effectiveness clinical trials through this FOA (please see NCCIH Clinical Trial Funding Opportunities instead). Investigators are strongly encouraged to discuss their research plans with NCCIH program staff prior to submitting their application.

NICHD:  Characterization of the cannabinoids and endocannabinoid system as potential targets for treatment of dysmenorrhea, vulvodynia, and chronic pelvic pain due to endometriosis and other gynecologic disorders.  Studies into the role of these systems in the management of spasticity, neuropathic pain, bone pain, musculoskeletal pain and pain secondary to other disabling conditions. Cannabinoids and endocannabinoid system and their therapeutic and adverse effects in pregnancy and its outcomes.

NIAAA: Alcohol abuse/dependence causes increased pain sensitivity and neuropathic pain. The role of endocannabinoids in mediating the actions of alcohol in inducing and regulating pain responses will be the primary interest.

Deadlines:  standard dates and standard AIDS dates apply


Filed Under: Funding Opportunities