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.