**3. The entourage effect**

The entourage effect is defined as the act by which compounds (both cannabis phytochemicals and compounds from the endogenous cannabinoid system) augment or support the effects of major cannabinoids, for example, Δ9-THC, CBD, 2-arachidonoyl-glycerol (2-AG) [33, 34]. This phenomenon has been likened to an orchestra where 'many musicians support and harmonise the melody provided by the soloists' [34]. Compounds can exert synergistic effects through several mechanisms, for example by interacting with each other to improve bioavailability of beneficial compounds, or through combined actions on different therapeutic targets [35].

The concept of a cannabis entourage effect is largely based on anecdotal evidence from medicinal and recreational users attesting to the notion that cannabis 'works better' as a whole plant extract and its existence has been argued back and forth over time. However, there is evidence to suggest that the cannabis plant contains active ingredients as well as 'synergists' that boost drug effects above that of the isolated compound. Indeed, early description of a potential synergy between molecules in the cannabis plant came from a study in the 1970s that reported a 2–4 times greater deficits in parameters such as processing tasks and motor function in subjects administered Brazilian cannabis samples compared to Δ9-THC [36]. The phrase 'entourage effect' was first described in 1998 in response to the finding that certain endogenous molecules (2-linoleoyl-glycerol (2-LG) and 2-palmitoyl-glycerol (2-PG)) potentiated the effects of the endocannabinoid, 2-AG [33]. Interestingly, cultured hippocampal neurons exposed to CBD-rich plant extracts exhibit a significantly greater intracellular signalling response compared to CBD alone [37]. This provides preliminary (*in-vitro*) evidence that CBD-rich plant extracts exert greater effects on cells of the hippocampus (a region of the brain highly implicated in learning and memory) than isolated CBD. Overall, it may be possible to boost the pro-cognitive therapeutic efficacy of CBD through a synergistic approach. Studies show that cannabinoids other than CBD could confer beneficial effects on the brain through synergistic mechanisms, for example, the parent phytocannabinoid cannabigerol (CBG) exerted greater analgesic effects on mice than Δ9-THC alone, while CBG and cannabichromene (CBC) both have anti-depressant effects in rodents (reviewed in [38]) and CBG is neuroprotective in a mouse model of Huntington's Disease [39]. However, section 4 will focus on several key non-cannabinoid cannabis phytochemicals with promising evidence of positive effects on brain function.
