CRITICAL REVIEWS IN PLANT SCIENCES, 2016, VOL. 35, NOS. 5–6, 349–363

Doi : 10.1080/07352689.2016.1265363

The geographical and ecological range of Cannabis is unusually broad, with cultivated populations growing outdoors on every continent, except Antarctica, in a wide range of environments from sub-arctic to temperate to tropical, and from sea level to over 3000 m elevation (Clarke and Merlin, 2013; Glanzman, 2015). Feral or wild populations are also found as far north as the edge of the Arctic Circle in Eurasia, but they are most com- mon in well-drained soils of temperate continental eco- systems in Eurasia and North America, while tropical populations are absent or rare (Clarke and Merlin, 2013). The species contains extensive phytochemical diversity, particularly in cannabinoid and terpenoid pro- files (Hillig and Mahlberg, 2004; Hillig, 2005), and it also shows extensive diversity of morphological and life-his- tory characteristics, further fueling debate regarding the taxonomic status and origins of Cannabis domestication. One distinctive feature of the Cannabis genus is the production of a tremendous diversity of compounds called cannabinoids, they are so named because they are not produced in high levels in any other plant species (Bauer et al., 2008). Cannabinoids are a group of at least 74 known C21 terpenophenolic compounds (ElSohly and Slade, 2005; Radwan et al., 2008) responsible for many reported medicinal and psychoactive effects of Cannabis consumption (Poklis et al., 2010). Some estimates for the total number of phytocannabinoids range to well over a hundred (Mehmedic et al., 2010), though this number includes breakdown products as well as compounds found at extremely low levels. The plants produce a non- psychoactive carboxylic acid form of these compounds, which requires heating to convert cannabinoids into the psychoactive decarboxylated forms. Interestingly, these compounds have pronounced neurological effects on a wide range of vertebrate and invertebrate taxa suggesting an ancient origin of the endocannabinoid receptors, per- haps as old as the last common ancestor of all extant bilat- erians over 500 MYA (McPartland et al., 2006). The plant compounds thus produced have the potential to affect a broad range of metazoans, though their ecological func- tions in nature are not well understood. Indeed, the sug- gested roles for these compounds include many biotic and abiotic defenses, such as suppression of pathogens and herbivores, protection from UV radiation damage, and attraction of seed dispersers. These hypotheses about the selective benefits of cannabinoid production remain speculative, as none has been conclusively verified to date. We know more, however, about the evolutionary forces during cultivation and domestication.

In particular, high delta-9-tetrahydrocannabinolic acid (THCA) content has been selected for (Mechoulam and Gaoni, 1967). When heated, THCA is converted to delta- 9-tetrahydrocannabinol (THC), which has potent psycho- active (Volkow et al., 2014), appetite-stimulating (Berry and Mechoulam, 2002), analgesic (Zogopoulos et al., 2013) and antiemetic (Tramer et al., 2001) effects. These effects are mediated through interactions with human endocannabinoid CB1 receptors found in the brain (Di Marzo et al., 2004), and CB2 receptors, which are concen- trated in peripheral tissues (Pacher and Mechoulam, 2011). Other THC receptor binding locations are hypoth- esized as well (De Petrocellis et al., 2011). After several decades of accelerated clandestine cultivation technique and breeding improvements, some modern lines can now yield dried unpollinated pistillate inflorescence material that contains over 30% THCA by dry weight (Swift et al., 2013). However, other cannabinoids may also be present in high concentrations. In particular, high cannabidiolic acid (CBDA) plants are used in some hashish prepara- tions (Rustichelli et al., 1996; Hanus et al., 2016) and are presently in high demand as an antiseizure therapy (Devinsky et al., 2014). In contrast with THC, which acts as a partial agonist of the CB1 and CB2 receptors, CBD does not have strong psychoactive properties as THC, but instead it has antagonist activity on agonists of the CB1 and CB2 receptors (Pertwee, 2008). Thus, the two most abundant cannabinoids produced in Cannabis have, to some degree, opposing neurological effects.

THCA and CBDA are alternative products of a shared precursor, cannabigerolic acid (CBGA) (Fellermeier et al., 2001). A single locus with co-dominant alleles was pro- posed to explain patterns of inheritance for THCA to CBDA ratios (de Meijer et al., 2003; Staginnus et al., 2014). However more recent quantitative trait loci (QTL) map- ping experiments (Weiblen et al., 2015), expression studies (Onofri et al., 2015), and genomic analyses (van Bakel et al., 2011) paint a more complex scenario with several linked paralogs responsible for the various THCA and CBDA phenotypes. Other cannabinoids such as cannabi- gerol (CBG) (Borrelli et al., 2014), cannabichromene (CBC) (Izzo et al., 2012), and delta-9-tetrahydrocannabi- varin (THCV) (Mcpartland et al., 2015) demonstrate phar- macological promise, and can also be produced at high levels by the plant (de Meijer and Hammond, 2005; de Meijer and Hammond, 2016; de Meijer et al., 2008). Addi- tionally, Cannabis secondary metabolites such as terpe- noids and flavonoids likely contribute to therapeutic or psychoactive effects (Russo, 2011). For example, b-myr- cene, humulene, and linalool are proposed to produce sed- ative effects associated with specific varieties (Hazekamp and Fischedick, 2012).

(…)