TABLE 1:

Research Priorities – Pre-clinical aspects of cannabinoid pharmacology and the endocannabinoid system

• Further research to elucidate the neurobiology of endocannabinoid signaling in relation to pathological pain processing, and investigation of additional potential analgesic targets within, or interacting with, the endocannabinoid system.

• Nuanced understanding of cannabinoid receptor signaling and the role of allosteric modulation and biased agonism of the cannabinoid receptors.

• Better alignment between compounds tested in clinical trials with those tested preclinically, to allow improved understanding of translational (and back translational) pharmacology of targeting the endocannabinoid system for analgesia.

• Investigation of the pharmacology of cannabinoids beyond THC, including CBD and other phytocannabinoids.

• Detailed characterization of pharmacokinetic properties of cannabinoids, and determination of pharmacokinetic-pharmacodynamic (PK-PD) relationship between plasma concentrations, effect site concentrations, and antinociception in the context of specific preclinical models.

• Optimization of modes and formulations of drug delivery to achieve consistent drug exposure at the site of action.

• Further investigation of the analgesic potential of cannabinoid receptors and targets outside the CNS, to circumvent unwanted central side effects.

• Understanding the physiological interactions between the endogenous cannabinoid and opioid systems in pain modulation.

• Further research on the role of the endocannabinoid system and cannabinoids in modulating the affective-motivational and cognitive dimensions of pain processing and pain experience.

• Improved external validity of animal models and outcome measures used to determine antinociceptive effects (particularly long-term ones) of cannabinoids and endocannabinoid system modulators

• Improved rigor and transparency of design, conduct, analysis and reporting of preclinical studies.