In the previous century, scientists started to uncover the mechanisms that underlie the pharmacology of cannabis. The discovery of cannabinoids and of the endocannabinoid system (ECS) represented turning points in terms of explaining the effects of cannabis on the human body. As discussed in a previous newsletter, the current understanding is that THC and CBD are the two main agents responsible for most of the effects observed after cannabis consumption¹. However, the story might be more complicated, and fascinating, than that.

The first research paper revealing the complexity of the issue was investigating the ECS in rodents, with a focus on the endocannabinoid 2-Arachidonoylglycerol (2-AG, newsletter 6). Researchers discovered that the administration of 2-AG, together with two related glycerol compounds, modified the effects of 2-AG alone in mice². The reason this result was very surprising is that these two “entourage” compounds are devoid of activity towards CB1 or CB2 receptors! Therefore, the authors hypothesised that there might be several mechanisms through which compounds related to cannabinoids influence their potency and, therefore, their overall effect. In other words, they hypothesised the existence of the “entourage effect”, where a mixture of cannabinoids produces an effect different from the simple combination of each individual component³.

As you can imagine, this notion has implications for cannabis and its therapeutic use as well. Most of the cannabinoids present in the plant (about 120 different compounds) are not psychoactive and display only very limited activity against cannabinoids receptors. Is it possible that they are still contributing to the effect of cannabis when consumed? If so, what are the mechanisms that underlie this phenomenon? Can we harness these interactions to produce novel, cannabis-based medications that go beyond THC and CBD? Is the entourage effect responsible for the differences that many users claim exist between strains with comparable levels of THC? The research on the topic is still ongoing and no definitive answer exists yet. In 2002 pure THC was compared to cannabis preparations, both smoked and orally administered, without any notable difference in plasma concentrations or subjective experience being reported by participants⁴. In another study, cannabis containing varying levels of CBD or cannabichromene (CBC) was administered to participants together with THC, revealing no change in the experience of subjects⁵. 

Although interesting, such studies present limitations; for instance, the concentrations of cannabinoids used (including THC) are much lower than what is present in cannabis sourced from the black market³. There are also reports in literature that support the notion that other cannabinoids can modulate the activity of THC. For instance, a double-blind randomised trial demonstrated that the combination of THC and CBD, but not THC alone, was able to significantly reduce pain in cancer patients resistant to opioid treatment⁶. In another report it was shown that hippocampal neurons react differently when exposed to a combination of THC and CBD than to either cannabinoid alone⁷.

As if the story wasn’t complex enough, terpenoids, the compounds responsible for the fragrance of cannabis, can also have effects on the brain. The amount of literature on their pharmacology is not overwhelming, but they do for instance appear to generate marked behavioural responses in mice when exposed⁸. Interestingly, a recent report investigated the modulatory effect of some terpenoids on the responses of cannabinoid receptors to THC, CBD and 2-AG, ruling out an interaction at this level⁹. The authors cannot exclude the existence of an “entourage” interaction between terpenoids and cannabinoids, but recognize that it is likely to be mediated by molecular targets other than cannabinoid receptors. This notion can be extended also to interactions among cannabinoids. Although understudied, many of these compounds have recognised targets outside of cannabinoid receptors, which can mediate physiological effects outside of the endocannabinoid system¹⁰.

Unfortunately, most of the literature is dominated by THC and CBD studies, and further research exploring other combinations of cannabinoids is needed in order to understand to what extent, if any, the “entourage effect” differentiates whole cannabis preparations to THC-only preparations. This could expand the range of conditions in which cannabis-based medication can be useful, as well as improving existing formulations. Finally, the investigation of the entourage effect among cannabis metabolites could promote similar research in other therapeutically relevant plants, providing similar benefits to the ones described above.