Up to 80% of adults in the US with chronic pain report inadequate treatment. Investigation into the analgesic actions of Cannabis have focused on the primary constituent 9-tetrahydrocannabinol (THC) and its synthetic counterparts, however the psychoactive effects of the cannabinoid receptor agonists hamper their use in the clinic, as have questions regarding their overall efficacy. Recently the second most abundant phytocannabinoid cannabidiol (CBD) was added to THC clinically (the buccal spray Sativex) to decrease THC's psychoactive effects, but clinical evidence challenges the success of this concept as recent reports demonstrate that Sativex produces similar subjective and other effects to THC, including "high" and "marijuana-like", and impairs cognition and attention. At the same time, a handful of preclinical reports have now shown robust analgesic efficacy of CBD administered alone. The long-term goal of this research is to identify highly efficacious and safe cannabinoid-based pharmacotherapies for the treatment of neuropathic pain using innovative preclinical pain, abuse liability, and cognition assays. The objective of the R03 Behavioral Science Track Award application is to quantitatively determine by dose-addition analysis the relative efficacies of two putative analgesic Cannabis constituents, CBD and THC, alone and in combination using stimulus- and non- evoked neuropathic pain assays and adverse effect tests. The central hypothesis is that CBD is a more efficacious anti-neuropathic agent than THC and that CBD+THC combinations will produce additive, but not synergistic, analgesic effects. We hypothesize that CBD will not produce dependence or cognitive impairment as compared with THC, and that CBD+THC combinations will be similar to THC alone on these adverse effect measures.
Aim 1 will demonstrate that CBD is more effective than THC in producing a conditioned place preference in mice experiencing chemotherapy-induced neuropathic pain. Results will also demonstrate a lack of synergy between CBD and THC's analgesic actions.
Aim 2 will demonstrate CBD's improved safety profile over CBD. Chronic administration of THC alone or THC+CBD will lead to physical dependence while acute treatments will produce cognitive impairments. CBD alone will not produce physical dependence or affect cognitive performance. The proposed research is significant and innovative because it diverges from the current focus on CBD as a putative adjunct to THC for pain relief toward the identification of CBD alone as an anti-neuropathic agent with improved efficacy and safely. Innovation is also achieved with the incorporation of rigorous quantification by use of dose-addition analysis across several behavioral endpoints to provide a comprehensive comparison of the safety and efficacy of THC, CBD and THC+CBD. Innovation is also achieved by the combined use of stimulus-evoked and non-evoked assays for neuropathic pain testing as well as more novel abuse liability and cognitive assays for CB-based pharmacotherapies.
Cannabinoid-based analgesic therapeutics have been under investigation for some time but psychoactive effects of agonists such as THC hamper their use in the clinic, as do questions related to their overall efficacy. The major contributions of the proposed research will therefore be the preclinical identification of the non-toxic, non-psychoactive Cannabis constituent cannabidiol (CBD) as a highly effective and safe analgesic on its own, particularly for treatment of neuropathic pain, with an overall improved profile above current THC or THC+CBD therapies. The project is relevant to NIDA's mission to cross-cut the influence of pain on drug abuse and addiction as it will identify CBD as an effective, non-addictive analgesic for treatment of neuropathic pain.