Cannabis-Based Medicines and Pain: A Review of Potential Synergistic and Entourage Effects

The recent legalization of medicinal cannabis in several jurisdictions has spurred the development of therapeutic formulations for chronic pain. Unlike pure delta-9-tetrahydrocannabinol (THC), full-spectrum products contain naturally occurring cannabinoids and have been reported to show improved efficacy or tolerability, attributed to synergy between cannabinoids and other components in the cannabis plant. Although 'synergy' indicates that two or more active compounds may produce an additive or combined effect greater than their individual analgesic effect, potentiation of the biological effect of a compound by related but inactive compounds, in combination, was termed the 'entourage effect'. Here, we review current evidence for potential synergistic and entourage effects of cannabinoids in pain relief. However, definitive clinical trials and in vitro functional studies are still required. Plain Language Summary: Lay abstract Cannabis-based medicines have been used for millennia, and recent studies have identified their main constituents for pain relief, delta-9-tetrahydrocannabinol and cannabidiol (CBD). However, cannabis contains hundreds of other potentially active compounds, and their combined effects may underlie the reported preference of some patients for cannabinoid extracts, rather than pure delta-9-tetrahydrocannabinol. Further, cannabis-based drugs may interact with endocannabinoids, which are produced within the body and are related to the compounds found in cannabis. We have reviewed the evidence for cannabinoids in combination, and with other drugs, for pain relief. Although there is some evidence for an advantage of combinations, basic research and clinical studies are still required.