8.2. Cannabis synergy

To date, research into Cannabis-based medicines has primarily focussed on single isolated cannabinoid compounds. However, some studies show that combinations of various Cannabis components display greater biological activity than single compounds, suggesting that whole plant extracts may be more effective than purified phytocannabinoids (Russo, 2011). The increased activity of whole Cannabis extracts may be due to the synergism between various cannabinoid and non-cannabinoid components, which has been termed ‘the entourage effect’ (Russo, 2011). Proposed mechanisms underlying the entourage effect in Cannabisinclude activation of multiple molecular targets, enhanced bio-availability or solubility of compounds, and neutralisation of adverse events (Wagner and Ulrich-Merzenich, 2009). Exploiting Cannabis synergy to develop new medicines based on whole-plant extracts may be beneficial for a range of pharmaceutical applications.
In epilepsy, the addition of non-THC, non-CBD Cannabismetabolites may enhance the anticonvulsant effects of existing treatments. In a mouse model of epilepsy, the content of minor phytocannabinoid compounds in a high-CBD plant extract treatment affected seizure incidence and survival rates, suggesting that specific combinations of phytocannabinoids may be more effective than single purified compounds (Berman et al., 2018). Furthermore, a meta-analysis of observational clinical studies on epilepsy treatment reported that CBD-rich plant extracts reduced seizure frequency in patients at doses lower than those used in clinical trials of Epidiolex. The CBD-rich plant extract also produced significantly fewer adverse effects, likely due to the lower dose required (Devinsky et al., 2017; Pamplona et al., 2018; Thiele et al., 2018).
The benefits of phytocannabinoids for pain management have been well-established. However, the analgesic effects of Cannabis may be enhanced by combining different Cannabis bioactive compounds. The analgesic and anti-inflammatory effects of CBD occur only within a very limited dose range, but this bell-shaped dose-response was overcome when CBD was combined with a Cannabis extract (Gallily et al., 2015). Another study showed that a Cannabis extract high in THC provided no benefit for intractable cancer pain, while nabiximols, a whole extract CBD/THC combination significantly reduced pain in cancer patients (Johnson et al., 2010).
Whole-plant extracts may also be preferable to single phytocannabinoids for the treatment of mood disorders. Several phytocannabinoids, including THC, CBD and CBC, appear to have antidepressant and/or anti-anxiety effects, possibly due to modulation of the endocannabinoid system and/or modulation of serotonin receptors (Crippa et al., 2011; Poleszak et al., 2018; Zanelati et al., 2010). Other non-cannabinoid Cannabis compounds, such as the terpenoid limonene, also exhibit antidepressant effects, and lemon oil, which contains high quantities of limonene displays anti-stress and anxiolytic properties (Komiya et al., 2006; Piccinelli et al., 2015; Russo, 2011). Plant extracts containing both cannabinoids and terpenoids may be the most effective Cannabis-based treatment option for psychopharmacological applications.
Synergistic effects are also potentially beneficial for cancer treatment. In breast cancer cell lines and animal models, a Cannabis extract produced enhanced anti-tumour effects compared to purified THC, possibly due to the presence of other cannabinoid compounds (Blasco-Benito et al., 2018). Another study reported that whole plant extracts reduced cancer cell survival and proliferation more effectively than pure THC, across a range of cancer cell types (Baram et al., 2019). Notably, one study found that cancer cells were killed most effectively when treated with phytocannabinoids and terpenoids at ratios similar to those found naturally in the plant (Namdar et al., 2019).
The above findings suggest that, for the treatment of various medical conditions, producing a range of Cannabis varieties , or chemotypes, with varying phytochemical contents may constitute a more effective approach than developing new synthetic cannabinoid-based medicines. A greater understanding of the synergistic activities of different phytocannabinoids, terpenoids and other Cannabiscomponents is needed to identify the most effective combinations for various pharmaceutical applications.