8.1. Cannabis metabolites

Early investigations into the pharmacologic effects of THC led to the discovery of the human endogenous cannabinoid (endocannabinoid) system, which includes endogenous cannabinoid ligands, metabolic enzymes, and the two major cannabinoid receptors, CB1 and CB2 (Izzo et al., 2009). The modes of action of phytocannabinoids are complex, with individual compounds capable of acting at multiple molecular targets. THC modulates the activity of CB1 and CB2 but can also activate the transcription factor PPARγ and the TRP ion channel TRPA1 (Izzo et al., 2009). CBD, meanwhile, has low affinity for CB1 and CB2, but can modulate the activity of various components of the endocannabinoid system. Furthermore, like THC, CBD can target PPARγ and TRPA1, as well as the G-protein coupled receptors GPR55 and GPR18, the TRP ion channels TRPV1, TRPV2 and TRPM8, and the serotonin receptor 5-HT1a(Izzo et al., 2009). By modulating various signalling pathways involved in multiple diseases, phytocannabinoids have the potential to provide many therapeutic benefits.
The analgesic, antiemetic and anticonvulsant properties of phytocannabinoids are well-established (Whiting et al., 2015). Growing evidence suggests that Cannabismetabolites also produce anti-inflammatory, anti-depressant, anxiolytic and anti-cancer effects (Atalay et al., 2019; Fraguas-Sánchez and Torres-Suárez, 2018; Poleszak et al., 2018; Śledziński et al., 2018). Synthetically produced cannabinoids can mimic the effects of plant-derived compounds, and many countries have approved synthetic cannabinoids for medicinal use. Dronabinol and nabilone, synthetic forms of THC, are approved for the treatment of chemotherapy-induced nausea and vomiting, and for appetite stimulation in AIDS-associated anorexia (Freeman et al., 2019). However, plant-derived medicines have also been developed, namely Epidiolex, a purified form of CBD for the treatment of severe forms of epilepsy, and Sativex, a Cannabis extract containing THC and CBD for the management of pain and spasticity in multiple sclerosis (Freeman et al., 2019).
Additionally, Cannabis contains many non-cannabinoid metabolites, including terpenoids, flavonoids, ligand amides and stilbenes (Pollastro et al., 2018b). Of these, the terpenoids have been most extensively studied, and display many therapeutic effects (Russo, 2011). Due to growing evidence that various Cannabis bioactive compounds act synergistically to produce therapeutic effects (Russo, 2011), a greater understanding of the pharmacological contributions of differentCannabis metabolites will be needed to develop the most effectiveCannabis -based medicines.